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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">An international collaborative family-based whole genome quantitative trait linkage scan for myopic refractive error</title><author><name sortKey="Abbott, Diana" sort="Abbott, Diana" uniqKey="Abbott D" first="Diana" last="Abbott">Diana Abbott</name><affiliation><nlm:aff id="aff1">Center for Human Genetics, Duke University Medical Center, Durham, NC</nlm:aff></affiliation></author><author><name sortKey="Li, Yi Ju" sort="Li, Yi Ju" uniqKey="Li Y" first="Yi-Ju" last="Li">Yi-Ju Li</name><affiliation><nlm:aff id="aff1">Center for Human Genetics, Duke University Medical Center, Durham, NC</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC</nlm:aff></affiliation></author><author><name sortKey="Guggenheim, Jeremy A" sort="Guggenheim, Jeremy A" uniqKey="Guggenheim J" first="Jeremy A." last="Guggenheim">Jeremy A. Guggenheim</name><affiliation><nlm:aff id="aff3">School of Optometry and Vision Sciences, Cardiff University, Cardiff, Wales, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Metlapally, Ravikanth" sort="Metlapally, Ravikanth" uniqKey="Metlapally R" first="Ravikanth" last="Metlapally">Ravikanth Metlapally</name><affiliation><nlm:aff id="aff1">Center for Human Genetics, Duke University Medical Center, Durham, NC</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Department of Ophthalmology, Duke University Eye Center, Durham, NC</nlm:aff></affiliation></author><author><name sortKey="Malecaze, Francois" sort="Malecaze, Francois" uniqKey="Malecaze F" first="Francois" last="Malecaze">Francois Malecaze</name><affiliation><nlm:aff id="aff5">Toulouse University Hospital, Toulouse, France</nlm:aff></affiliation></author><author><name sortKey="Calvas, Patrick" sort="Calvas, Patrick" uniqKey="Calvas P" first="Patrick" last="Calvas">Patrick Calvas</name><affiliation><nlm:aff id="aff5">Toulouse University Hospital, Toulouse, France</nlm:aff></affiliation></author><author><name sortKey="Rosenberg, Thomas" sort="Rosenberg, Thomas" uniqKey="Rosenberg T" first="Thomas" last="Rosenberg">Thomas Rosenberg</name><affiliation><nlm:aff id="aff6">Kennedy Centre, Gordon Norrie Centre and National Eye Clinic, Glostrup, Denmark</nlm:aff></affiliation></author><author><name sortKey="Paget, Sandrine" sort="Paget, Sandrine" uniqKey="Paget S" first="Sandrine" last="Paget">Sandrine Paget</name><affiliation><nlm:aff id="aff5">Toulouse University Hospital, Toulouse, France</nlm:aff></affiliation></author><author><name sortKey="Zayats, Tetyana" sort="Zayats, Tetyana" uniqKey="Zayats T" first="Tetyana" last="Zayats">Tetyana Zayats</name><affiliation><nlm:aff id="aff3">School of Optometry and Vision Sciences, Cardiff University, Cardiff, Wales, United Kingdom</nlm:aff></affiliation><affiliation><nlm:aff id="aff7">Centre for Eye Research Australia, Department of Ophthalmology, University of Melbourne, Melbourne, Australia</nlm:aff></affiliation></author><author><name sortKey="Mackey, David A" sort="Mackey, David A" uniqKey="Mackey D" first="David A." last="Mackey">David A. Mackey</name><affiliation><nlm:aff id="aff7">Centre for Eye Research Australia, Department of Ophthalmology, University of Melbourne, Melbourne, Australia</nlm:aff></affiliation></author><author><name sortKey="Feng, Sheng" sort="Feng, Sheng" uniqKey="Feng S" first="Sheng" last="Feng">Sheng Feng</name><affiliation><nlm:aff id="aff1">Center for Human Genetics, Duke University Medical Center, Durham, NC</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC</nlm:aff></affiliation></author><author><name sortKey="Young, Terri L" sort="Young, Terri L" uniqKey="Young T" first="Terri L." last="Young">Terri L. Young</name><affiliation><nlm:aff id="aff1">Center for Human Genetics, Duke University Medical Center, Durham, NC</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Department of Ophthalmology, Duke University Eye Center, Durham, NC</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">22509102</idno><idno type="pmc">3324362</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3324362</idno><idno type="RBID">PMC:3324362</idno><date when="2012">2012</date><idno type="wicri:Area/Pmc/Corpus">002775</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002775</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">An international collaborative family-based whole genome quantitative trait linkage scan for myopic refractive error</title><author><name sortKey="Abbott, Diana" sort="Abbott, Diana" uniqKey="Abbott D" first="Diana" last="Abbott">Diana Abbott</name><affiliation><nlm:aff id="aff1">Center for Human Genetics, Duke University Medical Center, Durham, NC</nlm:aff></affiliation></author><author><name sortKey="Li, Yi Ju" sort="Li, Yi Ju" uniqKey="Li Y" first="Yi-Ju" last="Li">Yi-Ju Li</name><affiliation><nlm:aff id="aff1">Center for Human Genetics, Duke University Medical Center, Durham, NC</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC</nlm:aff></affiliation></author><author><name sortKey="Guggenheim, Jeremy A" sort="Guggenheim, Jeremy A" uniqKey="Guggenheim J" first="Jeremy A." last="Guggenheim">Jeremy A. Guggenheim</name><affiliation><nlm:aff id="aff3">School of Optometry and Vision Sciences, Cardiff University, Cardiff, Wales, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Metlapally, Ravikanth" sort="Metlapally, Ravikanth" uniqKey="Metlapally R" first="Ravikanth" last="Metlapally">Ravikanth Metlapally</name><affiliation><nlm:aff id="aff1">Center for Human Genetics, Duke University Medical Center, Durham, NC</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Department of Ophthalmology, Duke University Eye Center, Durham, NC</nlm:aff></affiliation></author><author><name sortKey="Malecaze, Francois" sort="Malecaze, Francois" uniqKey="Malecaze F" first="Francois" last="Malecaze">Francois Malecaze</name><affiliation><nlm:aff id="aff5">Toulouse University Hospital, Toulouse, France</nlm:aff></affiliation></author><author><name sortKey="Calvas, Patrick" sort="Calvas, Patrick" uniqKey="Calvas P" first="Patrick" last="Calvas">Patrick Calvas</name><affiliation><nlm:aff id="aff5">Toulouse University Hospital, Toulouse, France</nlm:aff></affiliation></author><author><name sortKey="Rosenberg, Thomas" sort="Rosenberg, Thomas" uniqKey="Rosenberg T" first="Thomas" last="Rosenberg">Thomas Rosenberg</name><affiliation><nlm:aff id="aff6">Kennedy Centre, Gordon Norrie Centre and National Eye Clinic, Glostrup, Denmark</nlm:aff></affiliation></author><author><name sortKey="Paget, Sandrine" sort="Paget, Sandrine" uniqKey="Paget S" first="Sandrine" last="Paget">Sandrine Paget</name><affiliation><nlm:aff id="aff5">Toulouse University Hospital, Toulouse, France</nlm:aff></affiliation></author><author><name sortKey="Zayats, Tetyana" sort="Zayats, Tetyana" uniqKey="Zayats T" first="Tetyana" last="Zayats">Tetyana Zayats</name><affiliation><nlm:aff id="aff3">School of Optometry and Vision Sciences, Cardiff University, Cardiff, Wales, United Kingdom</nlm:aff></affiliation><affiliation><nlm:aff id="aff7">Centre for Eye Research Australia, Department of Ophthalmology, University of Melbourne, Melbourne, Australia</nlm:aff></affiliation></author><author><name sortKey="Mackey, David A" sort="Mackey, David A" uniqKey="Mackey D" first="David A." last="Mackey">David A. Mackey</name><affiliation><nlm:aff id="aff7">Centre for Eye Research Australia, Department of Ophthalmology, University of Melbourne, Melbourne, Australia</nlm:aff></affiliation></author><author><name sortKey="Feng, Sheng" sort="Feng, Sheng" uniqKey="Feng S" first="Sheng" last="Feng">Sheng Feng</name><affiliation><nlm:aff id="aff1">Center for Human Genetics, Duke University Medical Center, Durham, NC</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC</nlm:aff></affiliation></author><author><name sortKey="Young, Terri L" sort="Young, Terri L" uniqKey="Young T" first="Terri L." last="Young">Terri L. Young</name><affiliation><nlm:aff id="aff1">Center for Human Genetics, Duke University Medical Center, Durham, NC</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Department of Ophthalmology, Duke University Eye Center, Durham, NC</nlm:aff></affiliation></author></analytic><series><title level="j">Molecular Vision</title><idno type="eISSN">1090-0535</idno><imprint><date when="2012">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Purpose</title><p>To investigate quantitative trait loci linked to refractive error, we performed a genome-wide quantitative trait linkage analysis using single nucleotide polymorphism markers and family data from five international sites.</p></sec><sec><title>Methods</title><p>Genomic DNA samples from 254 families were genotyped by the Center for Inherited Disease Research using the Illumina Linkage Panel IVb. Quantitative trait linkage analysis was performed on 225 Caucasian families and 4,656 markers after accounting for linkage disequilibrium and quality control exclusions. Two refractive quantitative phenotypes, sphere (SPH) and spherical equivalent (SE), were analyzed. The SOLAR program was used to estimate identity by descent probabilities and to conduct two-point and multipoint quantitative trait linkage analyses.</p></sec><sec><title>Results</title><p>We found 29 markers and 11 linkage regions reaching peak two-point and multipoint logarithms of the odds (LODs)>1.5. Four linkage regions revealed at least one LOD score greater than 2: chromosome 6q13–6q16.1 (LOD=1.96 for SPH, 2.18 for SE), chromosome 5q35.1–35.2 (LOD=2.05 for SPH, 1.80 for SE), chromosome 7q11.23–7q21.2 (LOD=1.19 for SPH, 2.03 for SE), and chromosome 3q29 (LOD=1.07 for SPH, 2.05 for SE). Among these, the chromosome 6 and chromosome 5 regions showed the most consistent results between SPH and SEM. Four linkage regions with multipoint scores above 1.5 are near or within the known myopia (MYP) loci of MYP3, MYP12, MYP14, and MYP16. Overall, we observed consistent linkage signals across the SPH and SEM phenotypes, although scores were generally higher for the SEM phenotype.</p></sec><sec><title>Conclusions</title><p>Our quantitative trait linkage analyses of a large myopia family cohort provided additional evidence for several known MYP loci, and identified two additional potential loci at chromosome 6q13–16.1 and chromosome 5q35.1–35.2 for myopia. These results will benefit the efforts toward determining genes for myopic refractive error.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Kempen, Jh" uniqKey="Kempen J">JH Kempen</name></author><author><name sortKey="Mitchell, P" uniqKey="Mitchell P">P Mitchell</name></author><author><name sortKey="Lee, Ke" uniqKey="Lee K">KE Lee</name></author><author><name sortKey="Tielsch, Jm" uniqKey="Tielsch J">JM Tielsch</name></author><author><name sortKey="Broman, At" uniqKey="Broman A">AT Broman</name></author><author><name sortKey="Taylor, Hr" uniqKey="Taylor H">HR Taylor</name></author><author><name sortKey="Ikram, Mk" uniqKey="Ikram M">MK Ikram</name></author><author><name sortKey="Congdon, Ng" uniqKey="Congdon N">NG Congdon</name></author><author><name sortKey="O Colmain, Bj" uniqKey="O Colmain B">BJ O'Colmain</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wensor, M" uniqKey="Wensor M">M Wensor</name></author><author><name sortKey="Mccarty, Ca" uniqKey="Mccarty C">CA McCarty</name></author><author><name sortKey="Taylor, Hr" uniqKey="Taylor H">HR Taylor</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Fan, Ds" uniqKey="Fan D">DS Fan</name></author><author><name sortKey="Lam, Ds" uniqKey="Lam D">DS Lam</name></author><author><name sortKey="Lam, Rf" uniqKey="Lam R">RF Lam</name></author><author><name sortKey="Lau, Jt" uniqKey="Lau J">JT Lau</name></author><author><name sortKey="Chong, Ks" uniqKey="Chong K">KS Chong</name></author><author><name sortKey="Cheung, Ey" uniqKey="Cheung E">EY Cheung</name></author><author><name sortKey="Lai, Ry" uniqKey="Lai R">RY Lai</name></author><author><name sortKey="Chew, Sj" uniqKey="Chew S">SJ Chew</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Vitale, S" uniqKey="Vitale S">S Vitale</name></author><author><name sortKey="Sperduto, D" uniqKey="Sperduto D">D Sperduto</name></author><author><name sortKey="Ferris, Fl" uniqKey="Ferris F">FL Ferris</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lam, Cs" uniqKey="Lam C">CS Lam</name></author><author><name sortKey="Goldschmidt, E" uniqKey="Goldschmidt E">E Goldschmidt</name></author><author><name sortKey="Edwards, Mh" uniqKey="Edwards M">MH Edwards</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Woo, Ww" uniqKey="Woo W">WW Woo</name></author><author><name sortKey="Lim, Ka" uniqKey="Lim K">KA Lim</name></author><author><name sortKey="Yang, H" uniqKey="Yang H">H Yang</name></author><author><name sortKey="Lim, Xy" uniqKey="Lim X">XY Lim</name></author><author><name sortKey="Liew, F" uniqKey="Liew F">F Liew</name></author><author><name sortKey="Lee, Ys" uniqKey="Lee Y">YS Lee</name></author><author><name sortKey="Saw, Sm" uniqKey="Saw S">SM Saw</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hornbeak, Dm" uniqKey="Hornbeak D">DM Hornbeak</name></author><author><name sortKey="Young, Tl" uniqKey="Young T">TL Young</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Goss, Da" uniqKey="Goss D">DA Goss</name></author><author><name sortKey="Winkler, Rl" uniqKey="Winkler R">RL Winkler</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ghafour, Im" uniqKey="Ghafour I">IM Ghafour</name></author><author><name sortKey="Allan, D" uniqKey="Allan D">D Allan</name></author><author><name sortKey="Foulds, Ws" uniqKey="Foulds W">WS Foulds</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pararajasegaram, R" uniqKey="Pararajasegaram R">R Pararajasegaram</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Saw, Sm" uniqKey="Saw S">SM Saw</name></author><author><name sortKey="Gazzard, G" uniqKey="Gazzard G">G Gazzard</name></author><author><name sortKey="Shih Yen, Ec" uniqKey="Shih Yen E">EC Shih-Yen</name></author><author><name sortKey="Chau, Wh" uniqKey="Chau W">WH Chau</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Teikari, Jm" uniqKey="Teikari J">JM Teikari</name></author><author><name sortKey="O Donnell, J" uniqKey="O Donnell J">J O'Donnell</name></author><author><name sortKey="Kaprio, J" uniqKey="Kaprio J">J Kaprio</name></author><author><name sortKey="Koskenvuo, M" uniqKey="Koskenvuo M">M Koskenvuo</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Sorsby, A" uniqKey="Sorsby A">A Sorsby</name></author><author><name sortKey="Leary, Ga" uniqKey="Leary G">GA Leary</name></author><author><name sortKey="Fraser, Gr" uniqKey="Fraser G">GR Fraser</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lyhne, N" uniqKey="Lyhne N">N Lyhne</name></author><author><name sortKey="Sjolie, Ak" uniqKey="Sjolie A">AK Sjolie</name></author><author><name sortKey="Kyvik, Ko" uniqKey="Kyvik K">KO Kyvik</name></author><author><name sortKey="Green, A" uniqKey="Green A">A Green</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hammond, Cj" uniqKey="Hammond C">CJ Hammond</name></author><author><name sortKey="Snieder, H" uniqKey="Snieder H">H Snieder</name></author><author><name sortKey="Gilbert, Ce" uniqKey="Gilbert C">CE Gilbert</name></author><author><name sortKey="Spector, Td" uniqKey="Spector T">TD Spector</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Guggenheim, Ja" uniqKey="Guggenheim J">JA Guggenheim</name></author><author><name sortKey="Kirov, G" uniqKey="Kirov G">G Kirov</name></author><author><name sortKey="Hodson, Sa" uniqKey="Hodson S">SA Hodson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Farbrother, Je" uniqKey="Farbrother J">JE Farbrother</name></author><author><name sortKey="Kirov, G" uniqKey="Kirov G">G Kirov</name></author><author><name sortKey="Owen, Mj" uniqKey="Owen M">MJ Owen</name></author><author><name sortKey="Guggenheim, Ja" uniqKey="Guggenheim J">JA Guggenheim</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hammond, Cj" uniqKey="Hammond C">CJ Hammond</name></author><author><name sortKey="Andrew, T" uniqKey="Andrew T">T Andrew</name></author><author><name sortKey="Mak, Yt" uniqKey="Mak Y">YT Mak</name></author><author><name sortKey="Spector, Td" uniqKey="Spector T">TD Spector</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wojciechowski, R" uniqKey="Wojciechowski R">R Wojciechowski</name></author><author><name sortKey="Moy, C" uniqKey="Moy C">C Moy</name></author><author><name sortKey="Ciner, E" uniqKey="Ciner E">E Ciner</name></author><author><name sortKey="Ibay, G" uniqKey="Ibay G">G Ibay</name></author><author><name sortKey="Reider, L" uniqKey="Reider L">L Reider</name></author><author><name sortKey="Bailey Wilson, Je" uniqKey="Bailey Wilson J">JE Bailey-Wilson</name></author><author><name sortKey="Stambolian, D" uniqKey="Stambolian D">D Stambolian</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wojciechowski, R" uniqKey="Wojciechowski R">R Wojciechowski</name></author><author><name sortKey="Stambolian, D" uniqKey="Stambolian D">D Stambolian</name></author><author><name sortKey="Ciner, E" uniqKey="Ciner E">E Ciner</name></author><author><name sortKey="Ibay, G" uniqKey="Ibay G">G Ibay</name></author><author><name sortKey="Holmes, Tn" uniqKey="Holmes T">TN Holmes</name></author><author><name sortKey="Bailey Wilson, Je" uniqKey="Bailey Wilson J">JE Bailey-Wilson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wojciechowski, R" uniqKey="Wojciechowski R">R Wojciechowski</name></author><author><name sortKey="Bailey Wilson, Je" uniqKey="Bailey Wilson J">JE Bailey-Wilson</name></author><author><name sortKey="Stambolian, D" uniqKey="Stambolian D">D Stambolian</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Stambolian, D" uniqKey="Stambolian D">D Stambolian</name></author><author><name sortKey="Ibay, G" uniqKey="Ibay G">G Ibay</name></author><author><name sortKey="Reider, L" uniqKey="Reider L">L Reider</name></author><author><name sortKey="Dana, D" uniqKey="Dana D">D Dana</name></author><author><name sortKey="Moy, C" uniqKey="Moy C">C Moy</name></author><author><name sortKey="Schlifka, M" uniqKey="Schlifka M">M Schlifka</name></author><author><name sortKey="Holmes, Tn" uniqKey="Holmes T">TN Holmes</name></author><author><name sortKey="Ciner, E" uniqKey="Ciner E">E Ciner</name></author><author><name sortKey="Bailey Wilson, Je" uniqKey="Bailey Wilson J">JE Bailey-Wilson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ciner, E" uniqKey="Ciner E">E Ciner</name></author><author><name sortKey="Ibay, G" uniqKey="Ibay G">G Ibay</name></author><author><name sortKey="Wojciechowski, R" uniqKey="Wojciechowski R">R Wojciechowski</name></author><author><name sortKey="Dana, D" uniqKey="Dana D">D Dana</name></author><author><name sortKey="Holmes, Tn" uniqKey="Holmes T">TN Holmes</name></author><author><name sortKey="Bailey Wilson, Je" uniqKey="Bailey Wilson J">JE Bailey-Wilson</name></author><author><name sortKey="Stambolian, D" uniqKey="Stambolian D">D Stambolian</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Stambolian, D" uniqKey="Stambolian D">D Stambolian</name></author><author><name sortKey="Ciner, Eb" uniqKey="Ciner E">EB Ciner</name></author><author><name sortKey="Reider, Lc" uniqKey="Reider L">LC Reider</name></author><author><name sortKey="Moy, C" uniqKey="Moy C">C Moy</name></author><author><name sortKey="Dana, D" uniqKey="Dana D">D Dana</name></author><author><name sortKey="Owens, R" uniqKey="Owens R">R Owens</name></author><author><name sortKey="Schlifka, M" uniqKey="Schlifka M">M Schlifka</name></author><author><name sortKey="Holmes, T" uniqKey="Holmes T">T Holmes</name></author><author><name sortKey="Ibay, G" uniqKey="Ibay G">G Ibay</name></author><author><name sortKey="Bailey Wilson, Je" uniqKey="Bailey Wilson J">JE Bailey-Wilson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Farbrother, Je" uniqKey="Farbrother J">JE Farbrother</name></author><author><name sortKey="Kirov, G" uniqKey="Kirov G">G Kirov</name></author><author><name sortKey="Owen, Mj" uniqKey="Owen M">MJ Owen</name></author><author><name sortKey="Pong Wong, R" uniqKey="Pong Wong R">R Pong-Wong</name></author><author><name sortKey="Haley, Cs" uniqKey="Haley C">CS Haley</name></author><author><name sortKey="Guggenheim, Ja" uniqKey="Guggenheim J">JA Guggenheim</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Li, Yj" uniqKey="Li Y">YJ Li</name></author><author><name sortKey="Guggenheim, Ja" uniqKey="Guggenheim J">JA Guggenheim</name></author><author><name sortKey="Bulusu, A" uniqKey="Bulusu A">A Bulusu</name></author><author><name sortKey="Metlapally, R" uniqKey="Metlapally R">R Metlapally</name></author><author><name sortKey="Abbott, D" uniqKey="Abbott D">D Abbott</name></author><author><name sortKey="Malecaze, F" uniqKey="Malecaze F">F Malecaze</name></author><author><name sortKey="Calvas, P" uniqKey="Calvas P">P Calvas</name></author><author><name sortKey="Rosenberg, T" uniqKey="Rosenberg T">T Rosenberg</name></author><author><name sortKey="Paget, S" uniqKey="Paget S">S Paget</name></author><author><name sortKey="Creer, Rc" uniqKey="Creer R">RC Creer</name></author><author><name sortKey="Kirov, G" uniqKey="Kirov G">G Kirov</name></author><author><name sortKey="Owen, Mj" uniqKey="Owen M">MJ Owen</name></author><author><name sortKey="Zhao, B" uniqKey="Zhao B">B Zhao</name></author><author><name sortKey="White, T" uniqKey="White T">T White</name></author><author><name sortKey="Mackey, Da" uniqKey="Mackey D">DA Mackey</name></author><author><name sortKey="Young, Tl" uniqKey="Young T">TL Young</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Boehnke, M" uniqKey="Boehnke M">M Boehnke</name></author><author><name sortKey="Cox, Nj" uniqKey="Cox N">NJ Cox</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Epstein, Mp" uniqKey="Epstein M">MP Epstein</name></author><author><name sortKey="Duren, Wl" uniqKey="Duren W">WL Duren</name></author><author><name sortKey="Boehnke, M" uniqKey="Boehnke M">M Boehnke</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mcpeek, Ms" uniqKey="Mcpeek M">MS McPeek</name></author><author><name sortKey="Sun, L" uniqKey="Sun L">L Sun</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="O Connell, Jr" uniqKey="O Connell J">JR O'Connell</name></author><author><name sortKey="Weeks, De" uniqKey="Weeks D">DE Weeks</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zaykin, Dv" uniqKey="Zaykin D">DV Zaykin</name></author><author><name sortKey="Zhivotovsky, La" uniqKey="Zhivotovsky L">LA Zhivotovsky</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Storey, Jd" uniqKey="Storey J">JD Storey</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Carlson, Cs" uniqKey="Carlson C">CS Carlson</name></author><author><name sortKey="Eberle, Ma" uniqKey="Eberle M">MA Eberle</name></author><author><name sortKey="Rieder, Mj" uniqKey="Rieder M">MJ Rieder</name></author><author><name sortKey="Yi, Q" uniqKey="Yi Q">Q Yi</name></author><author><name sortKey="Kruglyak, L" uniqKey="Kruglyak L">L Kruglyak</name></author><author><name sortKey="Nickerson, Da" uniqKey="Nickerson D">DA Nickerson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Almasy, L" uniqKey="Almasy L">L Almasy</name></author><author><name sortKey="Blangero, J" uniqKey="Blangero J">J Blangero</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Fulker, Dw" uniqKey="Fulker D">DW Fulker</name></author><author><name sortKey="Cherny, Ss" uniqKey="Cherny S">SS Cherny</name></author><author><name sortKey="Cardon, Lr" uniqKey="Cardon L">LR Cardon</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kong, A" uniqKey="Kong A">A Kong</name></author><author><name sortKey="Gudbjartsson, Df" uniqKey="Gudbjartsson D">DF Gudbjartsson</name></author><author><name sortKey="Sainz, J" uniqKey="Sainz J">J Sainz</name></author><author><name sortKey="Jonsdottir, Gm" uniqKey="Jonsdottir G">GM Jonsdottir</name></author><author><name sortKey="Gudjonsson, Sa" uniqKey="Gudjonsson S">SA Gudjonsson</name></author><author><name sortKey="Richardsson, B" uniqKey="Richardsson B">B Richardsson</name></author><author><name sortKey="Sigurdardottir, S" uniqKey="Sigurdardottir S">S Sigurdardottir</name></author><author><name sortKey="Barnard, J" uniqKey="Barnard J">J Barnard</name></author><author><name sortKey="Hallbeck, B" uniqKey="Hallbeck B">B Hallbeck</name></author><author><name sortKey="Masson, G" uniqKey="Masson G">G Masson</name></author><author><name sortKey="Shlien, A" uniqKey="Shlien A">A Shlien</name></author><author><name sortKey="Palsson, St" uniqKey="Palsson S">ST Palsson</name></author><author><name sortKey="Frigge, Ml" uniqKey="Frigge M">ML Frigge</name></author><author><name sortKey="Thorgeirsson, Te" uniqKey="Thorgeirsson T">TE Thorgeirsson</name></author><author><name sortKey="Gulcher, Jr" uniqKey="Gulcher J">JR Gulcher</name></author><author><name sortKey="Stefansson, K" uniqKey="Stefansson K">K Stefansson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Weeks, De" uniqKey="Weeks D">DE Weeks</name></author><author><name sortKey="Conley, Yp" uniqKey="Conley Y">YP Conley</name></author><author><name sortKey="Mah, Ts" uniqKey="Mah T">TS Mah</name></author><author><name sortKey="Paul, To" uniqKey="Paul T">TO Paul</name></author><author><name sortKey="Morse, L" uniqKey="Morse L">L Morse</name></author><author><name sortKey="Ngo Chang, J" uniqKey="Ngo Chang J">J Ngo-Chang</name></author><author><name sortKey="Dailey, Jp" uniqKey="Dailey J">JP Dailey</name></author><author><name sortKey="Ferrell, Re" uniqKey="Ferrell R">RE Ferrell</name></author><author><name sortKey="Gorin, Mb" uniqKey="Gorin M">MB Gorin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Morton, Ne" uniqKey="Morton N">NE Morton</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Mol Vis</journal-id><journal-id journal-id-type="iso-abbrev">Mol. Vis</journal-id><journal-id journal-id-type="publisher-id">MV</journal-id><journal-title-group><journal-title>Molecular Vision</journal-title></journal-title-group><issn pub-type="epub">1090-0535</issn><publisher><publisher-name>Molecular Vision</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">22509102</article-id><article-id pub-id-type="pmc">3324362</article-id><article-id pub-id-type="publisher-id">77</article-id><article-id pub-id-type="publisher-id">2011MOLVIS0361</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group></article-categories><title-group><article-title>An international collaborative family-based whole genome quantitative trait linkage scan for myopic refractive error</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Abbott</surname><given-names>Diana</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Li</surname><given-names>Yi-Ju</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Guggenheim</surname><given-names>Jeremy A.</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Metlapally</surname><given-names>Ravikanth</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Malecaze</surname><given-names>Francois</given-names></name><xref ref-type="aff" rid="aff5"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Calvas</surname><given-names>Patrick</given-names></name><xref ref-type="aff" rid="aff5"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Rosenberg</surname><given-names>Thomas</given-names></name><xref ref-type="aff" rid="aff6"><sup>6</sup></xref></contrib><contrib contrib-type="author"><name><surname>Paget</surname><given-names>Sandrine</given-names></name><xref ref-type="aff" rid="aff5"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Zayats</surname><given-names>Tetyana</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref><xref ref-type="aff" rid="aff7"><sup>7</sup></xref></contrib><contrib contrib-type="author"><name><surname>Mackey</surname><given-names>David A.</given-names></name><xref ref-type="aff" rid="aff7"><sup>7</sup></xref></contrib><contrib contrib-type="author"><name><surname>Feng</surname><given-names>Sheng</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Young</surname><given-names>Terri L.</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><aff id="aff1"><label>1</label>Center for Human Genetics, Duke University Medical Center, Durham, NC</aff><aff id="aff2"><label>2</label>Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC</aff><aff id="aff3"><label>3</label>School of Optometry and Vision Sciences, Cardiff University, Cardiff, Wales, United Kingdom</aff><aff id="aff4"><label>4</label>Department of Ophthalmology, Duke University Eye Center, Durham, NC</aff><aff id="aff5"><label>5</label>Toulouse University Hospital, Toulouse, France</aff><aff id="aff6"><label>6</label>Kennedy Centre, Gordon Norrie Centre and National Eye Clinic, Glostrup, Denmark</aff><aff id="aff7"><label>7</label>Centre for Eye Research Australia, Department of Ophthalmology, University of Melbourne, Melbourne, Australia</aff></contrib-group><author-notes><fn><p>The first two authors contributed equally to the work</p></fn><corresp id="cor1">Correspondence to: Terri L. Young, Center for Human Genetics, Duke University Medical Center, DUMC Box 3445, Durham, NC, 27710; Phone: (919) 684-1808; FAX: (919) 684-0906; email: <email xlink:href="terri.young@duke.edu">terri.young@duke.edu</email></corresp></author-notes><pub-date pub-type="collection"><year>2012</year></pub-date><pub-date pub-type="epub"><day>26</day><month>3</month><year>2012</year></pub-date><volume>18</volume><fpage>720</fpage><lpage>729</lpage><history><date date-type="received"><day>19</day><month>8</month><year>2011</year></date><date date-type="accepted"><day>22</day><month>3</month><year>2012</year></date></history><permissions><copyright-statement>Copyright © 2012 Molecular Vision.</copyright-statement><copyright-year>2012</copyright-year><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/3.0/"><license-p>This is an open-access article distributed under the terms of the
Creative Commons Attribution License, which permits unrestricted use,
distribution, and reproduction in any medium, provided the original
work is properly cited.</license-p></license></permissions><abstract><sec><title>Purpose</title><p>To investigate quantitative trait loci linked to refractive error, we performed a genome-wide quantitative trait linkage analysis using single nucleotide polymorphism markers and family data from five international sites.</p></sec><sec><title>Methods</title><p>Genomic DNA samples from 254 families were genotyped by the Center for Inherited Disease Research using the Illumina Linkage Panel IVb. Quantitative trait linkage analysis was performed on 225 Caucasian families and 4,656 markers after accounting for linkage disequilibrium and quality control exclusions. Two refractive quantitative phenotypes, sphere (SPH) and spherical equivalent (SE), were analyzed. The SOLAR program was used to estimate identity by descent probabilities and to conduct two-point and multipoint quantitative trait linkage analyses.</p></sec><sec><title>Results</title><p>We found 29 markers and 11 linkage regions reaching peak two-point and multipoint logarithms of the odds (LODs)>1.5. Four linkage regions revealed at least one LOD score greater than 2: chromosome 6q13–6q16.1 (LOD=1.96 for SPH, 2.18 for SE), chromosome 5q35.1–35.2 (LOD=2.05 for SPH, 1.80 for SE), chromosome 7q11.23–7q21.2 (LOD=1.19 for SPH, 2.03 for SE), and chromosome 3q29 (LOD=1.07 for SPH, 2.05 for SE). Among these, the chromosome 6 and chromosome 5 regions showed the most consistent results between SPH and SEM. Four linkage regions with multipoint scores above 1.5 are near or within the known myopia (MYP) loci of MYP3, MYP12, MYP14, and MYP16. Overall, we observed consistent linkage signals across the SPH and SEM phenotypes, although scores were generally higher for the SEM phenotype.</p></sec><sec><title>Conclusions</title><p>Our quantitative trait linkage analyses of a large myopia family cohort provided additional evidence for several known MYP loci, and identified two additional potential loci at chromosome 6q13–16.1 and chromosome 5q35.1–35.2 for myopia. These results will benefit the efforts toward determining genes for myopic refractive error.</p></sec></abstract><custom-meta-group><custom-meta><meta-name>GalleyStatus</meta-name><meta-value>Export to XML</meta-value></custom-meta><custom-meta><meta-name>corr-author</meta-name><meta-value>Young</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec><title>Introduction</title><p>Myopia, or nearsightedness, is the most common human eye disorder. Its diagnosis is based on refractive error biometrics, either negative sphere (SPH) or spherical equivalent (SE) (SE=SPH<sup>+</sup>1/2 cylinder) and is measured in diopters (D). Worldwide, individuals do not share the same myopic development risk, as the prevalence of myopia varies in different countries. Studies, primarily in adults but in some schoolchildren cohorts, have reported approximate prevalence rates of 17% in Australia, 26%–35% in the United States, and 27% in Western Europe [<xref ref-type="bibr" rid="r1">1</xref>–<xref ref-type="bibr" rid="r4">4</xref>]. Higher prevalence rates of 71%–96% have been reported in Asian countries such as Japan, Taiwan, Hong Kong, and Singapore [<xref ref-type="bibr" rid="r5">5</xref>–<xref ref-type="bibr" rid="r7">7</xref>]. Having myopia can significantly impact one’s daily life. High-grade levels of myopic refractive error (e.g., SEM or SPH less than −5.00 D) have associated ocular comorbidities of increased risk of premature cataracts, glaucoma, retinal detachment, and macular chorioretinal degeneration [<xref ref-type="bibr" rid="r1">1</xref>,<xref ref-type="bibr" rid="r8">8</xref>–<xref ref-type="bibr" rid="r13">13</xref>]. Myopia clearly is a significant global public health problem.</p><p>The genetic basis of myopia is supported by familial aggregation, segregation, and twin studies. High heritability estimates have been reported for SEM (0.5–0.96) [<xref ref-type="bibr" rid="r14">14</xref>–<xref ref-type="bibr" rid="r18">18</xref>] and axial length (AL) (0.40–0.94) [<xref ref-type="bibr" rid="r14">14</xref>–<xref ref-type="bibr" rid="r18">18</xref>]. The relative risk of myopia in siblings of a person with myopia has been estimated to be 5–20 for high myopia (SEM ≤ −6.00 D), and 1.5–3 for lower degrees of myopia (SE: −1.00 to −3.00 D) [<xref ref-type="bibr" rid="r19">19</xref>,<xref ref-type="bibr" rid="r20">20</xref>]. To date, more than 18 myopia (MYP) genetic chromosomal loci (MYP1–MYP18 and other implicated chromosomal regions) have been reported by genome-wide linkage studies in families. Most regions (11 MYP loci) were mapped for high-grade myopia in limited pedigree linkage studies. Although quantitative refractive data are generally available on ascertained samples, very few studies have used these continuous traits to map quantitative trait loci (QTLs) for myopia.</p><p>Of the 18 MYP chromosomal loci identified, five (MYP7 [11p13], MYP8 [3q26], MYP9 [4q12], MYP10 [8p23], and MYP14 [1p34–36]) [<xref ref-type="bibr" rid="r21">21</xref>,<xref ref-type="bibr" rid="r22">22</xref>] were initially identified through quantitative trait linkage analysis using refractive error measurements (SPH and SE) as the traits. For example, the MYP7–MYP10 loci were identified using 221 dizygotic (DZ) twins from a classical twin study designed to investigate the heritability of refractive error. The strongest linkage signal was at chromosome 11p13, which contained the biologically relevant candidate gene paired box gene 6 (<italic>PAX6</italic>). In contrast to the twin study design, the MYP14 locus was a QTL found after 49 multigenerational Ashkenazi Jewish families ascertained for common myopia using SEM as the trait were analyzed [<xref ref-type="bibr" rid="r22">22</xref>]. No evidence of linkage to this region was found in the authors’ efforts to replicate this finding in a meta-analysis consisting of Old Order Amish, African American, and Caucasian subjects [<xref ref-type="bibr" rid="r23">23</xref>]. However, in a later effort to fine-map the MYP14 locus in a combined cohort of Old Order Amish and Ashkenazi Jewish families, replication of this locus was accomplished, and the QTL was narrowed to a 10 Mb area extending from chromosome 1p34.2 to chromosome 1p35.2 [<xref ref-type="bibr" rid="r24">24</xref>].</p><p>As was the case with localizing MYP14, successful efforts to find QTLs for refractive error have often used homogenous populations in genome-wide linkage studies. These homogenous populations have included Ashkenazi Jews [<xref ref-type="bibr" rid="r22">22</xref>–<xref ref-type="bibr" rid="r25">25</xref>], Caucasians [<xref ref-type="bibr" rid="r23">23</xref>,<xref ref-type="bibr" rid="r26">26</xref>], African Americans [<xref ref-type="bibr" rid="r23">23</xref>,<xref ref-type="bibr" rid="r26">26</xref>], and Old Order Amish [<xref ref-type="bibr" rid="r23">23</xref>,<xref ref-type="bibr" rid="r27">27</xref>], and different loci have been identified. For instance, MYP14 was not found in Caucasians, and 4q21 and 12q24 were found in Caucasians but not Ashkenazi Jews and Old Order Amish [<xref ref-type="bibr" rid="r21">21</xref>,<xref ref-type="bibr" rid="r22">22</xref>,<xref ref-type="bibr" rid="r28">28</xref>]. Overall, the QTL studies to date used either a small number of multigenerational pedigrees or twins. A more comprehensive and large-scale approach will help verify the existing regions.</p><p>This study is an international collaborative effort combining high-grade myopia pedigrees from five sites, leading to the largest family data set for myopia to date. We performed a genome-wide quantitative trait linkage scan using SPH and SEM directly and compared the results to known myopia loci. The outcomes of this study provide us with additional information regarding known genetic loci, and we have identified new myopia loci.</p></sec><sec sec-type="methods"><title>Methods</title><sec><title>Patients and families</title><p>As previously described [<xref ref-type="bibr" rid="r29">29</xref>], 254 multiplex families (at least two affected individuals per family) consisting of 1,411 subjects (47% male) were ascertained independently at five international sites. Collaboration in this retrospective analysis occurred after each program had already recruited subjects. For the quantitative analysis presented here, we analyzed the largest subset of this data, which comprised 225 Caucasian families and 1,168 subjects (47% male). Participating centers included Cardiff University in the UK (CARD), Duke University Medical Center in the United States (DUK), the Kennedy Institute of National Eye Clinic at Hellerup, Denmark (HEL), the University of Melbourne in Australia (MEL), and Toulouse University in France (TOU). Before recruiting subjects, all study sites obtained the appropriate institutional review board human subjects research study approvals. All principles of the Declaration of Helsinki were adhered to. Individuals were not included in the study if they had any ocular disease or insult that could predispose to myopia, such as retinopathy of prematurity, retinal dystrophy, corneal keratopathy, and any genetic syndromes that include myopia as a clinical phenotypic component. Licensed ophthalmologists or optometrists conducted complete eye examinations on all consenting subjects. At each study site, subjects filled out clinical and family history questionnaires. SPH and SEM quantitative phenotypes were obtained for each individual.</p></sec><sec><title>Sample preparation and genotyping</title><p>All subject genomic DNA samples were cataloged at the Duke University Center for Human Genetics (Duke CHG) and genotyped at the National Institutes of Health Center for Inherited Disease Research (CIDR). Most samples were extracted from blood (77.36%), while the remaining samples were derived from buccal mucosa (22.16%) or saliva specimens (0.48%). The genotyping platform used in this study was the Illumina Linkage Panel IVb consisting of 6,008 genome-wide single nucleotide polymorphisms (SNPs; <ext-link ext-link-type="uri" xlink:href="http://www.illumina.com/support/faqs.ilmn">Illumina</ext-link>). Following the CIDR genotyping protocol, each 96-well DNA sample plate included two Centre d’Etudes du Polymorphisme Humain (CEPH) DNA control samples and four replicates of subject DNA samples. In all, 1,411 subject DNA samples, 81 anonymous DNA replicates, and 87 CEPH DNA controls were genotyped in this study. The genotype data were transferred to the Duke CHG for data analysis.</p></sec><sec><title>Quality control and data cleaning</title><p>Following CIDR genotyping protocol, several quality control measures were implemented to determine the final set of markers released to the Duke CHG for analysis [<xref ref-type="bibr" rid="r29">29</xref>]. A total of 5,928 SNPs were released by the CIDR for data analysis. Of these markers, 5,903 had GeneCall scores (a measure of how close a genotype is to the center of the cluster of other samples assigned to the same genotypes) greater than 0.15, and the 5,903 markers were taken forward for analysis in the pedigrees.</p><p>To examine family relationships using <ext-link ext-link-type="uri" xlink:href="http://csg.sph.umich.edu/boehnke/relpair.php">RELPAIR</ext-link> [<xref ref-type="bibr" rid="r30">30</xref>,<xref ref-type="bibr" rid="r31">31</xref>] and <ext-link ext-link-type="uri" xlink:href="http://utstat.toronto.edu/sun/Software/Prest/prest3.02/">PREST</ext-link> [<xref ref-type="bibr" rid="r32">32</xref>], 700 markers with approximately equal inter-marker distances across the genome were selected. All family relationship errors were subsequently corrected, and the <ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/pubmed/9634505">PEDCHECK</ext-link> software program [<xref ref-type="bibr" rid="r33">33</xref>] was used to again check for Mendelian inconsistencies. When we found inconsistencies, we followed one of two options: 1) we assigned the missing genotypes within a family for the members directly involved in the Mendelian inconsistencies, or 2) we dropped an individual from further analysis if the family designations were ambiguous and therefore could not be reconciled.</p><p>All SNPs were tested for the Hardy–Weinberg equilibrium (HWE). Two data sets with unrelated samples were formed in which one affected individual sample per family was randomly selected to cluster within a designated affected group and one unaffected individual sample per family was selected to add to a designated unaffected group. The HWE was then assessed using an exact test implemented in the Genetic Data Analysis (<ext-link ext-link-type="uri" xlink:href="http://www.eeb.uconn.edu/people/plewis/software.php">GDA</ext-link>) program [<xref ref-type="bibr" rid="r34">34</xref>]. Using 3,200 permutations (the default setting for the GDA program), we estimated empirical p values for each marker. We used the <ext-link ext-link-type="uri" xlink:href="http://genomics.princeton.edu/storeylab/qvalue/">Q-VALUE</ext-link> program to correct for multiple testing [<xref ref-type="bibr" rid="r35">35</xref>]. A marker with a q value less than 0.2 was declared a significant deviation from the HWE and was excluded in the linkage analysis. At this point, 5,744 markers remained. To account for linkage disequilibrium among SNPs, we used <ext-link ext-link-type="uri" xlink:href="http://droog.gs.washington.edu/multiPopTagSelect.html">LDSelect</ext-link> to determine tagging SNPs for analysis with an r<sup>2</sup> cutoff of 0.16 [<xref ref-type="bibr" rid="r36">36</xref>]. Subsequently, we identified 4,656 tagging SNPs that comprised the final marker set that we defined for linkage analysis.</p></sec><sec><title>Whole genome quantitative trait linkage analysis</title><p>For this analysis, we investigated two phenotypes (SPH and SE) that were computed as the binocular average of measurements of the right and left eyes. These binocular averages for SPH and SEM were used directly for the quantitative analysis. When individuals have great discrepancies in SPH or SEM measurements between the eyes, this averaging can result in a muted linkage signal. For our data set, however, most individuals had similar SPH and SEM values for both eyes. Which refractive error parameter is the “correct” one to use for refractive error genetics study is unknown; therefore, we chose to use both measurements in our analyses. SPH and SEM are surrogates for axial length—a metric that was not consistently obtained for participants. Of the 1,004 individuals with SPH measurements available for both eyes, only 37, or 3.7%, could be classified as having one normal eye and one moderately myopic eye (−1.00 OD ≤ SPH≤−3.00 OD), and only two, or 0.2%, could be classified as having one normal or moderately myopic eye and one highly myopic eye (SPH≤−6.00 OD). For SE, the percentages of different myopia classifications between the two eyes were 2.1% and 0.3%, respectively. Individuals who were missing a measurement in at least one eye were assigned as missing for the phenotype of interest. We used the Sequential Oligogenic Linkage Analysis Routines (<ext-link ext-link-type="uri" xlink:href="http://www.soph.uab.edu/ssg/linkage/linkageanalysis">SOLAR</ext-link>) variance components procedure to perform quantitative trait linkage analysis using 4,656 tagging SNPs across the genome [<xref ref-type="bibr" rid="r37">37</xref>]. Under this procedure, the quantitative phenotypes SPH and SEM were defined as linear functions of the <italic>n</italic> QTLs (<italic>r<sub>i</sub></italic>) that influence the trait:</p><disp-formula><mml:math id="M1"><mml:mrow><mml:mi>S</mml:mi><mml:mi>P</mml:mi><mml:mi>H</mml:mi><mml:mtext> </mml:mtext><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:mi>S</mml:mi><mml:mi>E</mml:mi></mml:mrow><mml:mo>)</mml:mo></mml:mrow><mml:mo>=</mml:mo><mml:mo>µ</mml:mo><mml:mtext> </mml:mtext><mml:mo>+</mml:mo><mml:mtext> </mml:mtext><mml:mstyle mathvariant="bold" mathsize="normal"><mml:mi>X</mml:mi></mml:mstyle><mml:mi>β</mml:mi><mml:mtext> </mml:mtext><mml:mo>+</mml:mo><mml:mtext> </mml:mtext><mml:mo>∑</mml:mo><mml:mtext> </mml:mtext><mml:msub><mml:mi>r</mml:mi><mml:mi>i</mml:mi></mml:msub><mml:mtext> </mml:mtext><mml:mo>+</mml:mo><mml:mtext> </mml:mtext><mml:mi>e</mml:mi></mml:mrow></mml:math></disp-formula><p>where <bold>X</bold> is a matrix of covariates and β is the regression coefficient matrix for the covariates. Parameters that comprise the likelihood function of SPH or SEM include the identical by descent (IBD) probability for a marker linked to a QTL, the additive genetic variance attributable to the unobserved QTL (σ<sup>2</sup><italic><sub>q</sub></italic>), and other variance components. Using a likelihood-ratio test, <ext-link ext-link-type="uri" xlink:href="http://www.soph.uab.edu/ssg/linkage/linkageanalysis">SOLAR</ext-link> tests a null hypothesis of no linkage (σ<sup>2</sup><italic><sub>q</sub></italic>=0). <ext-link ext-link-type="uri" xlink:href="http://www.soph.uab.edu/ssg/linkage/linkageanalysis">SOLAR</ext-link> also calculates a logarithm of the odds (LOD) score as evidence of linkage to an individual marker for two-point analysis or to an imputed chromosomal position for multipoint analysis.</p><p>Before calculating the likelihood, locus-specific IBD information was computed for all pairs of relatives [<xref ref-type="bibr" rid="r37">37</xref>]. Following the premise of the Fulker et al. [<xref ref-type="bibr" rid="r38">38</xref>] method, the <ext-link ext-link-type="uri" xlink:href="http://www.soph.uab.edu/ssg/linkage/linkageanalysis">SOLAR</ext-link> multipoint mapping strategy uses the map distance between markers to compute the IBD information for a pair of relatives at a QTL linked to a marker. For our analysis, we used a Kosambi sex-averaged map obtained from <ext-link ext-link-type="uri" xlink:href="http://www.decode.com/services/fine-mapping-with-microsatellites.php">deCode</ext-link> [<xref ref-type="bibr" rid="r39">39</xref>]. The factor representing ascertainment sites was included as a house effect in our model to adjust for ascertainment bias. That is, potential differences across ascertainment centers were investigated in our analysis by treating center as a random effect in the variance component model. We originally included sex as a covariate in the polygenic model, but dropped it from the final model due to a lack of significance. We examined the normality of phenotypic distribution before the linkage analysis using a Q-Q plot to meet the underlying assumption of the variance component model. We investigated several transformations, and viewed plots of log-transformed data in Q-Q plots. To meet the criterion of normality, we used the following formulas: SPH<sub>new</sub>=4.3xlog<sub>10</sub>[-(SPH-0.25)] and SE<sub>new</sub>=4.4xlog<sub>10</sub>[-(SE-0.25)].</p></sec></sec><sec sec-type="results"><title>Results</title><p>Of 254 families typed by the CIDR, the largest subset comprised 225 Caucasian families. This subset included 1,168 subjects. SPH data for only one eye were available for 164 subjects, and 256 subjects had SEM data for only one eye. These individuals were therefore not included in quantitative phenotype SPH or SEM analytical assessments. Summary descriptive statistics information for the samples included in the QTL analysis is provided in <xref ref-type="table" rid="t1">Table 1</xref>.</p><table-wrap id="t1" position="float"><label>Table 1</label><caption><title>Data set Descriptive Statistics by Mean Refractive Error.</title></caption><table frame="hsides" rules="groups"><col width="204" span="1"></col><col width="124" span="1"></col><col width="199" span="1"></col><thead><tr><th valign="top" align="left" scope="col" rowspan="1" colspan="1"><bold>Characteristic</bold></th><th valign="top" align="center" scope="col" rowspan="1" colspan="1"><bold>Mean sphere data set</bold></th><th valign="top" align="center" scope="col" rowspan="1" colspan="1"><bold>Mean spherical equivalent data set</bold></th></tr></thead><tbody><tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1">Total Sample Size<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1004<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">912<hr></hr></td></tr><tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1">Number of Families<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">216<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">215<hr></hr></td></tr><tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1">Average Family Size ± SD<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">4.65±3.20<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">4.24 ±3.06<hr></hr></td></tr><tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1">Average Age of Subject ± SD (years)<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">42.55±19.97<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">43.10±20.08<hr></hr></td></tr><tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1">Number with Age Data<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">923<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">838<hr></hr></td></tr><tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1">Mean Refractive Error ± SD (Diopters)<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">−5.74±5.66<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">−5.36±5.57<hr></hr></td></tr><tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1">Heritability (h<sup>2</sup>)</td><td valign="top" align="center" rowspan="1" colspan="1">0.232±0.0720</td><td valign="top" align="center" rowspan="1" colspan="1">0.339±0.0772</td></tr></tbody></table></table-wrap><p>The heritability of SPH or SEM was highly significant (p=0.0001298 and p=0.0000006 for SPH and SE, respectively), with heritabilities of 23.2% (SPH) and 33.9% (SE). We used a threshold level of LOD≥1.50 to highlight promising initial linkage regions of interest for two-point and multipoint linkage analyses (<xref ref-type="table" rid="t2">Table 2</xref> and <xref ref-type="table" rid="t3">Table 3</xref>) [<xref ref-type="bibr" rid="r40">40</xref>].</p><table-wrap id="t2" position="float"><label>Table 2</label><caption><title>Summary of peak regions with LOD > 1.5 from two-point QTL analysis.</title></caption><table frame="hsides" rules="groups"><col width="79" span="1"></col><col width="69" span="1"></col><col width="96" span="1"></col><col width="79" span="1"></col><col width="147" span="1"></col><thead><tr><th valign="top" align="center" scope="col" rowspan="1" colspan="1"><bold>Chromosome</bold></th><th valign="top" align="center" scope="col" rowspan="1" colspan="1"><bold>Marker</bold></th><th valign="top" align="center" scope="col" rowspan="1" colspan="1"><bold>DECODE (cM)</bold></th><th valign="top" align="center" scope="col" rowspan="1" colspan="1"><bold>Mean sphere</bold></th><th valign="top" align="center" scope="col" rowspan="1" colspan="1"><bold>Mean spherical equivalent</bold></th></tr></thead><tbody><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1">1<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"><ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=720887">rs720887</ext-link><hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">103.33<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.09<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.68<hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1">2<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"><ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=925229">rs925229</ext-link><hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">47.88<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">0.97<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.62<hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1">2<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"><ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=1369842">rs1369842</ext-link><hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">198.07<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.42<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.71<hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1">3<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"><ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=1500530">rs1500530</ext-link><hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">128.84<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">0.72<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.6<hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1">5<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"><ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=925893">rs925893</ext-link><hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">129.69<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">0.33<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.54<hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1">5<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"><ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=4868073">rs4868073</ext-link><hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">183.33<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.27<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.52<hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1"> <hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"><ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=472959">rs472959</ext-link><hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">187.27<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.11<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.62<hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1">6<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"><ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=4960147">rs4960147</ext-link><hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">15.18<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.56<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.36<hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1">6<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"><ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=2213661">rs2213661</ext-link><hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">55.45<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.65<hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1">6<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"><ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=2000203">rs2000203</ext-link><hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">87.57<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.76<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.19<hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1"> <hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"><ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=3798425">rs3798425</ext-link><hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">88.55<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">0.84<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.86<hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1"> <hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"><ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=1457947">rs1457947</ext-link><hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">89.14<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.52<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.24<hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1"> <hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"><ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=932492">rs932492</ext-link><hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">90.62<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.22<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.88<hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1"> <hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"><ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=1059306">rs1059306</ext-link><hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">93.3<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.3<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.76<hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1"> <hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"><ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=1179900">rs1179900</ext-link><hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">96.1<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">0.6<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">2.13<hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1"> <hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"><ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=491112">rs491112</ext-link><hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">100.5<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">0.35<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.65<hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1">7<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"><ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=28156">rs28156</ext-link><hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">96.18<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.33<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">2.09<hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1">11<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"><ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=731365">rs731365</ext-link><hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">40.36<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.02<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.96<hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1">11<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"><ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=528638">rs528638</ext-link><hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">132.61<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.13<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.81<hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1"> <hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"><ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=570969">rs570969</ext-link><hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">150.15<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">0.72<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.54<hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1">12<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"><ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=417664">rs417664</ext-link><hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">15.85<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">0.91<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.54<hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1">12<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"><ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=2730550">rs2730550</ext-link><hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">138<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">0.9<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.84<hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1">15<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"><ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=278357">rs278357</ext-link><hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">22.65<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.17<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.73<hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1">15<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"><ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=1445020">rs1445020</ext-link><hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">71.05<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">0.28<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.58<hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1">15<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"><ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=7168948">rs7168948</ext-link><hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">133.2<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.55<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.59<hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1">18<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"><ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=770238">rs770238</ext-link><hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">6.63<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.04<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.6<hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1">19<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"><ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=1715093">rs1715093</ext-link><hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">12.18<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.13<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.67<hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1">19<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"><ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=1122713">rs1122713</ext-link><hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">36.79<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.38<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.95<hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1">22</td><td valign="top" align="center" rowspan="1" colspan="1"><ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=2399153">rs2399153</ext-link></td><td valign="top" align="center" rowspan="1" colspan="1">1.54</td><td valign="top" align="center" rowspan="1" colspan="1">1.19</td><td valign="top" align="center" rowspan="1" colspan="1">1.53</td></tr></tbody></table><table-wrap-foot><p>CentiMorgans=cM, <ext-link ext-link-type="uri" xlink:href="http://genome.ucsc.edu/cgi-bin/hgGateway">DECODE</ext-link> mapping position used.</p></table-wrap-foot></table-wrap><table-wrap id="t3" position="float"><label>Table 3</label><caption><title>Summary of the peak Regions with LOD > 1.5 from multipoint quantitative trait Locus analysis.</title></caption><table frame="hsides" rules="groups"><col width="79" span="1"></col><col width="153" span="1"></col><col width="96" span="1"></col><col width="90" span="1"></col><col width="146" span="1"></col><thead><tr><th valign="top" align="center" scope="col" rowspan="1" colspan="1"><bold>Chromosome</bold></th><th valign="top" align="center" scope="col" rowspan="1" colspan="1"><bold>Locus</bold></th><th valign="top" align="center" scope="col" rowspan="1" colspan="1"><bold>Marker</bold></th><th valign="top" align="center" scope="col" rowspan="1" colspan="1"><bold>DECODE (cM)</bold></th><th valign="top" align="center" scope="col" rowspan="1" colspan="1"><bold>Mean spherical equivalent</bold></th></tr></thead><tbody><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1">1<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1p31.1<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"><ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=655938">rs655938</ext-link><hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">98<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"> <hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1"> <hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">(near MYP14, 1p36)<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">Peak LOD score<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">100<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.69<hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1"> <hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"> <hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"><ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=1389790">rs1389790</ext-link><hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">103<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"> <hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1">2<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">2q33.1<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"><ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=997467">rs997467</ext-link><hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">197<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"> <hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1"> <hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">(near MYP12, q37.1)<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">Peak<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">198<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.25<hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1"> <hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"> <hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"><ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=970595">rs970595</ext-link><hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">199<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"> <hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1">3<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">3q29<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"><ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=790927">rs790927</ext-link><hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">214<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"> <hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1"> <hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"> <hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"><ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=1864668">rs1864668</ext-link> (Peak)<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">221<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.07<hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1">5<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">5p13.3<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"><ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=2034586">rs2034586</ext-link> Peak<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"> <hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"> <hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1"> <hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">(near MYP16,5p15.33–15.2)<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"><ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=1021711">rs1021711</ext-link><hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">49<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.51<hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1">5<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">5q35.1–35.2<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"><ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=1054998">rs1054998</ext-link><hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">180<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"> <hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1"> <hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"> <hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">Peak<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">188<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">2.05<hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1"> <hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"> <hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"><ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=1875189">rs1875189</ext-link><hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">192<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"> <hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1">6<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">6q13<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"><ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=1817255">rs1817255</ext-link><hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">85<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"> <hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1"> <hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"> <hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">Peak<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">88<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.96<hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1"> <hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">6q16.1<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">Peak<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">95<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.57<hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1"> <hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"> <hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"><ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=1040155">rs1040155</ext-link><hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">100<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"> <hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1">7<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">7q11.23<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"><ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=3135677">rs3135677</ext-link><hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">87<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"> <hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1"> <hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">to<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">Peak<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">97<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.19<hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1"> <hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">7q21.2<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"><ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=9008">rs9008</ext-link><hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">102<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"> <hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1">10<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">10p11.21<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"><ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=913167">rs913167</ext-link><hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">63<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"> <hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1"> <hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">To<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">Peak<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">64<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">1.68<hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1"> <hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">10q11.22<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"><ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=733488">rs733488</ext-link><hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">66<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"> <hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1">11<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">11q24.2<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"><ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=1944819">rs1944819</ext-link><hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">137<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"> <hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1"> <hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"> <hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">Peak<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">142<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">0.54<hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1"> <hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"> <hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"><ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=570969">rs570969</ext-link><hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">148<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"> <hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1">12<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">12q24.31<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"><ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=922873">rs922873</ext-link><hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">145<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1"> <hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1"> <hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">(near MYP3, 12q21–23)<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">Peak<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">151<hr></hr></td><td valign="top" align="center" rowspan="1" colspan="1">0.63<hr></hr></td></tr><tr><td valign="top" align="center" scope="row" rowspan="1" colspan="1"> </td><td valign="top" align="center" rowspan="1" colspan="1"> </td><td valign="top" align="center" rowspan="1" colspan="1"><ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=1388149">rs1388149</ext-link></td><td valign="top" align="center" rowspan="1" colspan="1">152</td><td valign="top" align="center" rowspan="1" colspan="1"> </td></tr></tbody></table><table-wrap-foot><p>CentiMorgans=cM.</p></table-wrap-foot></table-wrap><sec><title>Quantitative trait loci linkage regions for the sphere phenotype</title><p>Four markers across two chromosomes resulted in two-point LOD scores ≥ 1.5 (<xref ref-type="table" rid="t2">Table 2</xref>). Graphical results for the genome-wide linkage scan are depicted in <xref ref-type="fig" rid="f1">Figure 1</xref>, and promising linked markers and linkage regions are summarized in <xref ref-type="table" rid="t2">Table 2</xref> and <xref ref-type="table" rid="t3">Table 3</xref>. The <ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=2000203">rs2000203</ext-link> at 87.57 centiMorgans (cM; two-point LOD=1.76) and <ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=1457947">rs1457947</ext-link> at 89.14 cM (two-point LOD=1.52) on chromosome 6 are in close proximity to each other. These markers also fall within a linkage region identified by the Caucasian subset in our data when treating SPH as a binary trait [<xref ref-type="bibr" rid="r29">29</xref>]. However, none of these four markers are near known MYP loci reported previously (<xref ref-type="table" rid="t2">Table 2</xref>).</p><fig id="f1" fig-type="figure" position="float"><label>Figure 1</label><caption><p>Genome-wide linkage analysis results for mean sphere (SPH) measurements. Logarithm of the odds (LOD) scores are plotted on the y-axes and genetic distance in centiMorgans (cM) along each chromosome on the x-axes. Two analyses are shown: two-point and multipoint quantitative trait linkage.</p></caption><graphic xlink:href="mv-v18-720-f1"></graphic></fig><p>Five linkage regions on separate chromosomes contained peak multipoint LOD scores ≥ 1.5 (<xref ref-type="table" rid="t3">Table 3</xref>). <xref ref-type="fig" rid="f2">Figure 2</xref> depicts a clear multipoint peak for chromosome 5q35.1–5q35.2 extending from 180 to 192 cM with a maximum LOD of 2.05, which is supported by <ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=4868073">rs4868073</ext-link> (183.33 cM) with a two-point LOD score of 1.27. The second highest multipoint peak is on chromosome 6q13–6q16.1 (peak LOD=1.96, 88 cM), which showed a LOD score over 2 when the SEM was analyzed (see next section). Other regions of interest include chromosome 1p31.1 (peak multipoint LOD=1.69 at 100 cM), chromosome 10p11.21–10q11.22 (peak multipoint LOD=1.68 at 64 cM), and chromosome 5p13.3 (peak multipoint LOD=1.51 at 49 cM; <xref ref-type="fig" rid="f2">Figure 2</xref>). The chromosome 1p31.1 locus is close to the MYP14, located at 1p36, and the 5p13.3 locus is near a known myopia locus, MYP16, located at 5p15.33–5p15.2.</p><fig id="f2" fig-type="figure" position="float"><label>Figure 2</label><caption><p>Chromosome 5 linkage analysis results for mean sphere (SPH) and mean spherical equivalence (SE). Multipoint (MPT) and two-point (2PT) logarithm of the odds (LOD) score results are presented.</p></caption><graphic xlink:href="mv-v18-720-f2"></graphic></fig></sec><sec><title>Quantitative trait loci linkage regions for the spherical equivalent phenotype</title><p>The linkage analyses of the SEM derived more markers and linkage regions of interest. There are 26 markers across 12 chromosomes that resulted in two-point LOD scores ≥1.5, and eight linkage regions from eight chromosomes that contained peak multipoint LOD scores ≥1.5 (<xref ref-type="table" rid="t2">Table 2</xref> and <xref ref-type="table" rid="t3">Table 3</xref>, and <xref ref-type="fig" rid="f3">Figure 3</xref>). Similar to the SPH phenotype, the strongest evidence of linkage for the SEM occurred at chromosome 6q13–6q16.1 (peak two-point LOD=2.13 at <ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=1179900">rs1179900</ext-link> and peak multipoint LOD=2.18 at 95 cM) and chromosome 5q35.1–5q35.2 (peak two-point LOD=1.62 at 187.27 cM and peak multipoint LOD=1.80 at 188 cM). In particular, the chromosome 6q13–16.1 region is strongly supported by a set of seven markers with two-point LOD scores ranging from 1.19 to 2.13 (<xref ref-type="table" rid="t2">Table 2</xref>). The overall view of the two-point and multipoint linkage results for chromosome 6 is depicted in <xref ref-type="fig" rid="f4">Figure 4</xref>.</p><fig id="f3" fig-type="figure" position="float"><label>Figure 3</label><caption><p>Genome-wide linkage analysis results for mean spherical equivalent (SE) measurements. Logarithm of the odds (LOD) scores are plotted on the y-axes and genetic distance in centiMorgans (cM) along each chromosome on the x-axes. Two analyses are shown: two-point and multipoint quantitative trait linkage.</p></caption><graphic xlink:href="mv-v18-720-f3"></graphic></fig><fig id="f4" fig-type="figure" position="float"><label>Figure 4</label><caption><p>Chromosome 6 linkage analysis results for mean sphere (SPH) and mean spherical equivalence (SE). Multipoint (MPT) and two-point (2PT) logarithm of the odds (LOD) score results are presented.</p></caption><graphic xlink:href="mv-v18-720-f4"></graphic></fig><p>Two more regions showed LOD scores above 2: chromosome 3q29 (multipoint LOD=2.05 at 221 cM) and chromosome 7q11.23–7q21.2 (multipoint LOD=2.03 at 97 cM; <xref ref-type="table" rid="t3">Table 3</xref>). Overall, six out of 11 regions showed similar LOD score trends for the SPH and the SEM.</p><p>Among the 11 linkage regions outlined in <xref ref-type="table" rid="t3">Table 3</xref>, four loci are in close proximity to previously identified myopia loci. They are chromosome 1p31.1 for MYP14, chromosome 2q33.1 for MYP12, chromosome 5p13.3 for MYP16, and chromosome 12q24.31 for MYP3.</p></sec></sec><sec sec-type="discussion"><title>Discussion</title><p>We report a large-scale refractive error quantitative trait linkage study that used dense SNP genotyping as opposed to microsatellite markers. In this study, we identified two loci of high interest linked to myopic refractive error: (1) chromosome 6q13–6q16.1 with multipoint peak LOD scores of 1.96 for SPH and 2.18 for SEM and (2) chromosome 5q35.1–5q35.2 with multipoint peak LOD scores of 2.05 for SPH and 1.80 for SEM. The consistency of the LOD score significance derived from two different but similar measures of refractive error, SPH and SE, for these two loci. The chromosome 5q35.1–35.2 locus overlaps with a region that we reported previously using high myopia as a qualitative disease phenotype [<xref ref-type="bibr" rid="r29">29</xref>]. The chromosome 6q13–6q16.1 locus has not been previously reported as a linkage region for myopia in the literature.</p><p>Overall, our LOD scores are low (not achieving the standard significant threshold LOD ≥3) [<xref ref-type="bibr" rid="r41">41</xref>]. This is expected as we determined a relatively low residual heritability (24%–25%) of refractive error for our data set. Furthermore, since quantitative traits likely result from a confluence of factors including the involvement of several polymorphic genes and environmental conditions, the signal at a single QTL will not appear as strong given other factors acting on the trait. Despite these limitations, the pattern of our results still provides a good overview of refractive error loci across the genome.</p><p>In conducting our analysis, we recognized that an investigation of axial length, a major determinant of axial myopia, in our data might be insightful. Unfortunately, axial length data were collected for fewer than a third of our study participants (total sample size=266 compared to 1,004 and 912 for SPH and SE, respectively). Quantitative trait linkage analysis was conducted for the axial length data set, but no two-point or multipoint results exceeded a LOD threshold of 1.5. The power to detect a linkage signal for axial length was severely hampered by the low sample size.</p><p>In our previous report of linkage regions for high-grade myopia, the linkage regions were largely inconsistent between the analyses of the disease states defined by the SPH and the SEM [<xref ref-type="bibr" rid="r29">29</xref>]. When SPH and SEM are analyzed as quantitative traits, consistent results were found. This is expected, as the spreads of the SPH and SEM distributions are similar (SD: ±5.66 [SPH] versus ±5.57 [SE]). Most importantly, this shows the advantage of using quantitative traits in analyses. Comparatively, dichotomizing a distribution to a binary variable tends to lose power and adds phenotype state uncertainty when different clinical definitions of the affection status exist (e.g., SPH versus SE).</p><p>The present study provides important information. First, two new loci on chromosomes 5 and 6 are likely to be new chromosomal regions that link to myopic refractive errors. Second, our linkage analysis again replicated suggestive significance of the MYP3 locus on chromosome 12q. Clearly, this locus should undergo additional scrutiny in other data sets. Third, our analysis underscores the benefits of using refractive error as a quantitative trait for linkage, and demonstrates the advantage of using an SNP-based linkage screening protocol with higher marker density than conventional microsatellite markers to map new loci. The results of the present study of a large family data set using high-density SNPs for linkage scanning should aid in triaging candidate genes and loci for future genome-wide association studies and deep sequencing efforts.</p></sec></body><back><ack><title>Acknowledgments</title><p>We thank the members of the myopia families for their participation in this project. We thank the Center for Inherited Disease Research (CIDR) for their outstanding genotyping service. We thank Anuradha Bulusu for her statistical assistance. We thank Bei Zhao for her database administration assistance. This study was supported by grants from: the National Institute of Health (NIH; R01EY014685), NIH CIDR (N01-HG-65403), and Research to Prevent Blindness, Inc. Lew R. Wasserman Award to TLY; the College of Optometrists (NdB/TM/Gug/4/6/1) and the Sir Jules Thorn Trust (RSC047) to J.A.G.; and the Danish Organization of the Blind to T.R.</p></ack><ref-list><title>References</title><ref id="r1"><label>1</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kempen</surname><given-names>JH</given-names></name><name><surname>Mitchell</surname><given-names>P</given-names></name><name><surname>Lee</surname><given-names>KE</given-names></name><name><surname>Tielsch</surname><given-names>JM</given-names></name><name><surname>Broman</surname><given-names>AT</given-names></name><name><surname>Taylor</surname><given-names>HR</given-names></name><name><surname>Ikram</surname><given-names>MK</given-names></name><name><surname>Congdon</surname><given-names>NG</given-names></name><name><surname>O'Colmain</surname><given-names>BJ</given-names></name><collab>Eye Diseases Prevalence Research Group</collab></person-group><article-title>The prevalence of refractive errors among adults in the United States, Western Europe, and Australia.</article-title><source>Arch Ophthalmol</source><year>2004</year><volume>122</volume><fpage>495</fpage><lpage>505</lpage><pub-id pub-id-type="pmid">15078666</pub-id></element-citation></ref><ref id="r2"><label>2</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wensor</surname><given-names>M</given-names></name><name><surname>McCarty</surname><given-names>CA</given-names></name><name><surname>Taylor</surname><given-names>HR</given-names></name></person-group><article-title>Prevalence and risk factors of myopia in Victoria, Australia.</article-title><source>Arch Ophthalmol</source><year>1999</year><volume>117</volume><fpage>658</fpage><lpage>63</lpage><pub-id pub-id-type="pmid">10326965</pub-id></element-citation></ref><ref id="r3"><label>3</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Fan</surname><given-names>DS</given-names></name><name><surname>Lam</surname><given-names>DS</given-names></name><name><surname>Lam</surname><given-names>RF</given-names></name><name><surname>Lau</surname><given-names>JT</given-names></name><name><surname>Chong</surname><given-names>KS</given-names></name><name><surname>Cheung</surname><given-names>EY</given-names></name><name><surname>Lai</surname><given-names>RY</given-names></name><name><surname>Chew</surname><given-names>SJ</given-names></name></person-group><article-title>Prevalence, incidence, and progression of myopia of school children in Hong Kong.</article-title><source>Invest Ophthalmol Vis Sci</source><year>2004</year><volume>45</volume><fpage>1071</fpage><lpage>5</lpage><pub-id pub-id-type="pmid">15037570</pub-id></element-citation></ref><ref id="r4"><label>4</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Vitale</surname><given-names>S</given-names></name><name><surname>Sperduto</surname><given-names>D</given-names></name><name><surname>Ferris</surname><given-names>FL</given-names></name></person-group><article-title>Increased prevalence of myopia in the United States Between 1971–1972 and 1999–2004.</article-title><source>Arch Ophthalmol</source><year>2009</year><volume>127</volume><fpage>1632</fpage><lpage>9</lpage><pub-id pub-id-type="pmid">20008719</pub-id></element-citation></ref><ref id="r5"><label>5</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lam</surname><given-names>CS</given-names></name><name><surname>Goldschmidt</surname><given-names>E</given-names></name><name><surname>Edwards</surname><given-names>MH</given-names></name></person-group><article-title>Prevalence of myopia in local and international schools in Hong Kong.</article-title><source>Optom Vis Sci</source><year>2004</year><volume>81</volume><fpage>317</fpage><lpage>22</lpage><pub-id pub-id-type="pmid">15181356</pub-id></element-citation></ref><ref id="r6"><label>6</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Woo</surname><given-names>WW</given-names></name><name><surname>Lim</surname><given-names>KA</given-names></name><name><surname>Yang</surname><given-names>H</given-names></name><name><surname>Lim</surname><given-names>XY</given-names></name><name><surname>Liew</surname><given-names>F</given-names></name><name><surname>Lee</surname><given-names>YS</given-names></name><name><surname>Saw</surname><given-names>SM</given-names></name></person-group><article-title>Refractive errors in medical students in Singapore.</article-title><source>Singapore Med J</source><year>2004</year><volume>45</volume><fpage>470</fpage><lpage>4</lpage><pub-id pub-id-type="pmid">15455167</pub-id></element-citation></ref><ref id="r7"><label>7</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hornbeak</surname><given-names>DM</given-names></name><name><surname>Young</surname><given-names>TL</given-names></name></person-group><article-title>Myopia genetics: a review of current research and emerging trends.</article-title><source>Curr Opin Ophthalmol</source><year>2009</year><volume>20</volume><fpage>356</fpage><lpage>62</lpage><pub-id pub-id-type="pmid">19587595</pub-id></element-citation></ref><ref id="r8"><label>8</label><mixed-citation publication-type="book">Curtin BJ. The Myopias: Basic Science and Clinical Management. Philadelphia: Harper & Row; 1985.</mixed-citation></ref><ref id="r9"><label>9</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Goss</surname><given-names>DA</given-names></name><name><surname>Winkler</surname><given-names>RL</given-names></name></person-group><article-title>Progression of myopia in youth: age of cessation.</article-title><source>Am J Optom Physiol Opt</source><year>1983</year><volume>60</volume><fpage>651</fpage><lpage>8</lpage><pub-id pub-id-type="pmid">6624863</pub-id></element-citation></ref><ref id="r10"><label>10</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ghafour</surname><given-names>IM</given-names></name><name><surname>Allan</surname><given-names>D</given-names></name><name><surname>Foulds</surname><given-names>WS</given-names></name></person-group><article-title>Common causes of blindness and visual handicap in the west of Scotland.</article-title><source>Br J Ophthalmol</source><year>1983</year><volume>67</volume><fpage>209</fpage><lpage>13</lpage><pub-id pub-id-type="pmid">6830738</pub-id></element-citation></ref><ref id="r11"><label>11</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Pararajasegaram</surname><given-names>R</given-names></name></person-group><article-title>VISION 2020-the right to sight: from strategies to action.</article-title><source>Am J Ophthalmol</source><year>1999</year><volume>128</volume><fpage>359</fpage><lpage>60</lpage><pub-id pub-id-type="pmid">10511033</pub-id></element-citation></ref><ref id="r12"><label>12</label><mixed-citation publication-type="book">Tokoro T, Sato A. Results of investigation of pathologic myopia in Japan. Report of myopic chorioretinal atrophy. Ministry of Health and Welfare Tokyo. 1982;32–35.</mixed-citation></ref><ref id="r13"><label>13</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Saw</surname><given-names>SM</given-names></name><name><surname>Gazzard</surname><given-names>G</given-names></name><name><surname>Shih-Yen</surname><given-names>EC</given-names></name><name><surname>Chau</surname><given-names>WH</given-names></name></person-group><article-title>Myopia and associated pathological complications.</article-title><source>Ophthalmic Physiol Opt</source><year>2005</year><volume>25</volume><fpage>381</fpage><lpage>91</lpage><pub-id pub-id-type="pmid">16101943</pub-id></element-citation></ref><ref id="r14"><label>14</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Teikari</surname><given-names>JM</given-names></name><name><surname>O'Donnell</surname><given-names>J</given-names></name><name><surname>Kaprio</surname><given-names>J</given-names></name><name><surname>Koskenvuo</surname><given-names>M</given-names></name></person-group><article-title>Impact of heredity in myopia.</article-title><source>Hum Hered</source><year>1991</year><volume>41</volume><fpage>151</fpage><lpage>6</lpage><pub-id pub-id-type="pmid">1937488</pub-id></element-citation></ref><ref id="r15"><label>15</label><mixed-citation publication-type="book">Sorsby A, Sheriden M, Leary GA. Refraction and its components in twins. Spec. Rep. Ser. Med. Res. Coun., Lond., no. 303, H.M.S.O. 1962.</mixed-citation></ref><ref id="r16"><label>16</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Sorsby</surname><given-names>A</given-names></name><name><surname>Leary</surname><given-names>GA</given-names></name><name><surname>Fraser</surname><given-names>GR</given-names></name></person-group><article-title>Family studies on ocular refraction and its components.</article-title><source>J Med Genet</source><year>1966</year><volume>3</volume><fpage>269</fpage><lpage>73</lpage><pub-id pub-id-type="pmid">16178083</pub-id></element-citation></ref><ref id="r17"><label>17</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lyhne</surname><given-names>N</given-names></name><name><surname>Sjolie</surname><given-names>AK</given-names></name><name><surname>Kyvik</surname><given-names>KO</given-names></name><name><surname>Green</surname><given-names>A</given-names></name></person-group><article-title>The importance of genes and environment for ocular refraction and its determiners: a population based study among 20–45 year old twins.</article-title><source>Br J Ophthalmol</source><year>2001</year><volume>85</volume><fpage>1470</fpage><lpage>6</lpage><pub-id pub-id-type="pmid">11734523</pub-id></element-citation></ref><ref id="r18"><label>18</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hammond</surname><given-names>CJ</given-names></name><name><surname>Snieder</surname><given-names>H</given-names></name><name><surname>Gilbert</surname><given-names>CE</given-names></name><name><surname>Spector</surname><given-names>TD</given-names></name></person-group><article-title>Genes and environment in refractive error: the twin eye study.</article-title><source>Invest Ophthalmol Vis Sci</source><year>2001</year><volume>42</volume><fpage>1232</fpage><lpage>6</lpage><pub-id pub-id-type="pmid">11328732</pub-id></element-citation></ref><ref id="r19"><label>19</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Guggenheim</surname><given-names>JA</given-names></name><name><surname>Kirov</surname><given-names>G</given-names></name><name><surname>Hodson</surname><given-names>SA</given-names></name></person-group><article-title>The heritability of high myopia: a reanalysis of Goldschmidt's data.</article-title><source>J Med Genet</source><year>2000</year><volume>37</volume><fpage>227</fpage><lpage>31</lpage><pub-id pub-id-type="pmid">10777361</pub-id></element-citation></ref><ref id="r20"><label>20</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Farbrother</surname><given-names>JE</given-names></name><name><surname>Kirov</surname><given-names>G</given-names></name><name><surname>Owen</surname><given-names>MJ</given-names></name><name><surname>Guggenheim</surname><given-names>JA</given-names></name></person-group><article-title>Family aggregation of high myopia: estimation of the sibling recurrence risk ratio.</article-title><source>Invest Ophthalmol Vis Sci</source><year>2004</year><volume>45</volume><fpage>2873</fpage><lpage>8</lpage><pub-id pub-id-type="pmid">15326097</pub-id></element-citation></ref><ref id="r21"><label>21</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hammond</surname><given-names>CJ</given-names></name><name><surname>Andrew</surname><given-names>T</given-names></name><name><surname>Mak</surname><given-names>YT</given-names></name><name><surname>Spector</surname><given-names>TD</given-names></name></person-group><article-title>A susceptibility locus for myopia in the normal population is linked to the PAX6 gene region on chromosome 11: a genomewide scan of dizygotic twins.</article-title><source>Am J Hum Genet</source><year>2004</year><volume>75</volume><fpage>294</fpage><lpage>304</lpage><pub-id pub-id-type="pmid">15307048</pub-id></element-citation></ref><ref id="r22"><label>22</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wojciechowski</surname><given-names>R</given-names></name><name><surname>Moy</surname><given-names>C</given-names></name><name><surname>Ciner</surname><given-names>E</given-names></name><name><surname>Ibay</surname><given-names>G</given-names></name><name><surname>Reider</surname><given-names>L</given-names></name><name><surname>Bailey-Wilson</surname><given-names>JE</given-names></name><name><surname>Stambolian</surname><given-names>D</given-names></name></person-group><article-title>Genomewide scan in Ashkenazi Jewish families demonstrates evidence of linkage of ocular refraction to a QTL on chromosome 1p36.</article-title><source>Hum Genet</source><year>2006</year><volume>119</volume><fpage>389</fpage><lpage>99</lpage><pub-id pub-id-type="pmid">16501916</pub-id></element-citation></ref><ref id="r23"><label>23</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wojciechowski</surname><given-names>R</given-names></name><name><surname>Stambolian</surname><given-names>D</given-names></name><name><surname>Ciner</surname><given-names>E</given-names></name><name><surname>Ibay</surname><given-names>G</given-names></name><name><surname>Holmes</surname><given-names>TN</given-names></name><name><surname>Bailey-Wilson</surname><given-names>JE</given-names></name></person-group><article-title>Genomewide linkage scans for ocular refraction and meta-analysis of four populations in the Myopia Family Study.</article-title><source>Invest Ophthalmol Vis Sci</source><year>2009</year><volume>50</volume><fpage>2024</fpage><lpage>32</lpage><pub-id pub-id-type="pmid">19151385</pub-id></element-citation></ref><ref id="r24"><label>24</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wojciechowski</surname><given-names>R</given-names></name><name><surname>Bailey-Wilson</surname><given-names>JE</given-names></name><name><surname>Stambolian</surname><given-names>D</given-names></name></person-group><article-title>Fine-mapping of candidate region in Amish and Ashkenazi families confirms linkage of refractive error to a QTL on 1p34-p36.</article-title><source>Mol Vis</source><year>2009</year><volume>15</volume><fpage>1398</fpage><lpage>406</lpage><pub-id pub-id-type="pmid">19626131</pub-id></element-citation></ref><ref id="r25"><label>25</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Stambolian</surname><given-names>D</given-names></name><name><surname>Ibay</surname><given-names>G</given-names></name><name><surname>Reider</surname><given-names>L</given-names></name><name><surname>Dana</surname><given-names>D</given-names></name><name><surname>Moy</surname><given-names>C</given-names></name><name><surname>Schlifka</surname><given-names>M</given-names></name><name><surname>Holmes</surname><given-names>TN</given-names></name><name><surname>Ciner</surname><given-names>E</given-names></name><name><surname>Bailey-Wilson</surname><given-names>JE</given-names></name></person-group><article-title>Genome-wide scan of additional Jewish families confirms linkage of a myopia susceptibility locus to chromosome 22q12.</article-title><source>Mol Vis</source><year>2006</year><volume>12</volume><fpage>1499</fpage><lpage>505</lpage><pub-id pub-id-type="pmid">17167407</pub-id></element-citation></ref><ref id="r26"><label>26</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ciner</surname><given-names>E</given-names></name><name><surname>Ibay</surname><given-names>G</given-names></name><name><surname>Wojciechowski</surname><given-names>R</given-names></name><name><surname>Dana</surname><given-names>D</given-names></name><name><surname>Holmes</surname><given-names>TN</given-names></name><name><surname>Bailey-Wilson</surname><given-names>JE</given-names></name><name><surname>Stambolian</surname><given-names>D</given-names></name></person-group><article-title>Genome-wide scan of African-American and White families for linkage to myopia.</article-title><source>Am J Ophthalmol</source><year>2009</year><volume>147</volume><fpage>512</fpage><lpage>7</lpage><pub-id pub-id-type="pmid">19026404</pub-id></element-citation></ref><ref id="r27"><label>27</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Stambolian</surname><given-names>D</given-names></name><name><surname>Ciner</surname><given-names>EB</given-names></name><name><surname>Reider</surname><given-names>LC</given-names></name><name><surname>Moy</surname><given-names>C</given-names></name><name><surname>Dana</surname><given-names>D</given-names></name><name><surname>Owens</surname><given-names>R</given-names></name><name><surname>Schlifka</surname><given-names>M</given-names></name><name><surname>Holmes</surname><given-names>T</given-names></name><name><surname>Ibay</surname><given-names>G</given-names></name><name><surname>Bailey-Wilson</surname><given-names>JE</given-names></name></person-group><article-title>Genome-wide scan for myopia in the Old Order Amish.</article-title><source>Am J Ophthalmol</source><year>2005</year><volume>140</volume><fpage>469</fpage><lpage>76</lpage><pub-id pub-id-type="pmid">16084785</pub-id></element-citation></ref><ref id="r28"><label>28</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Farbrother</surname><given-names>JE</given-names></name><name><surname>Kirov</surname><given-names>G</given-names></name><name><surname>Owen</surname><given-names>MJ</given-names></name><name><surname>Pong-Wong</surname><given-names>R</given-names></name><name><surname>Haley</surname><given-names>CS</given-names></name><name><surname>Guggenheim</surname><given-names>JA</given-names></name></person-group><article-title>Linkage analysis of the genetic loci for high myopia on 18p, 12q, and 17q in 51 U.K. families.</article-title><source>Invest Ophthalmol Vis Sci</source><year>2004</year><volume>45</volume><fpage>2879</fpage><lpage>85</lpage><pub-id pub-id-type="pmid">15326098</pub-id></element-citation></ref><ref id="r29"><label>29</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Li</surname><given-names>YJ</given-names></name><name><surname>Guggenheim</surname><given-names>JA</given-names></name><name><surname>Bulusu</surname><given-names>A</given-names></name><name><surname>Metlapally</surname><given-names>R</given-names></name><name><surname>Abbott</surname><given-names>D</given-names></name><name><surname>Malecaze</surname><given-names>F</given-names></name><name><surname>Calvas</surname><given-names>P</given-names></name><name><surname>Rosenberg</surname><given-names>T</given-names></name><name><surname>Paget</surname><given-names>S</given-names></name><name><surname>Creer</surname><given-names>RC</given-names></name><name><surname>Kirov</surname><given-names>G</given-names></name><name><surname>Owen</surname><given-names>MJ</given-names></name><name><surname>Zhao</surname><given-names>B</given-names></name><name><surname>White</surname><given-names>T</given-names></name><name><surname>Mackey</surname><given-names>DA</given-names></name><name><surname>Young</surname><given-names>TL</given-names></name></person-group><article-title>An international collaborative family-based whole-genome linkage scan for high-grade myopia.</article-title><source>Invest Ophthalmol Vis Sci</source><year>2009</year><volume>50</volume><fpage>3116</fpage><lpage>27</lpage><pub-id pub-id-type="pmid">19324860</pub-id></element-citation></ref><ref id="r30"><label>30</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Boehnke</surname><given-names>M</given-names></name><name><surname>Cox</surname><given-names>NJ</given-names></name></person-group><article-title>Accurate inference of relationships in sib-pair linkage studies.</article-title><source>Am J Hum Genet</source><year>1997</year><volume>61</volume><fpage>423</fpage><lpage>9</lpage><pub-id pub-id-type="pmid">9311748</pub-id></element-citation></ref><ref id="r31"><label>31</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Epstein</surname><given-names>MP</given-names></name><name><surname>Duren</surname><given-names>WL</given-names></name><name><surname>Boehnke</surname><given-names>M</given-names></name></person-group><article-title>Improved inference of relationship for pairs of individuals.</article-title><source>Am J Hum Genet</source><year>2000</year><volume>67</volume><fpage>1219</fpage><lpage>31</lpage><pub-id pub-id-type="pmid">11032786</pub-id></element-citation></ref><ref id="r32"><label>32</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>McPeek</surname><given-names>MS</given-names></name><name><surname>Sun</surname><given-names>L</given-names></name></person-group><article-title>Statistical tests for detection of misspecified relationships by use of genome-screen data.</article-title><source>Am J Hum Genet</source><year>2000</year><volume>66</volume><fpage>1076</fpage><lpage>94</lpage><pub-id pub-id-type="pmid">10712219</pub-id></element-citation></ref><ref id="r33"><label>33</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>O'Connell</surname><given-names>JR</given-names></name><name><surname>Weeks</surname><given-names>DE</given-names></name></person-group><article-title>PedCheck: a program for identification of genotype incompatibilities in linkage analysis.</article-title><source>Am J Hum Genet</source><year>1998</year><volume>63</volume><fpage>259</fpage><lpage>66</lpage><pub-id pub-id-type="pmid">9634505</pub-id></element-citation></ref><ref id="r34"><label>34</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Zaykin</surname><given-names>DV</given-names></name><name><surname>Zhivotovsky</surname><given-names>LA</given-names></name></person-group><article-title>Ranks of genuine associations in whole-genome scans.</article-title><source>Genetics</source><year>2005</year><volume>171</volume><fpage>813</fpage><lpage>23</lpage><pub-id pub-id-type="pmid">16020784</pub-id></element-citation></ref><ref id="r35"><label>35</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Storey</surname><given-names>JD</given-names></name></person-group><article-title>A direct approach to false discovery rates.</article-title><source>J R Stat Soc, B</source><year>2002</year><volume>64</volume><fpage>479</fpage><lpage>98</lpage></element-citation></ref><ref id="r36"><label>36</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Carlson</surname><given-names>CS</given-names></name><name><surname>Eberle</surname><given-names>MA</given-names></name><name><surname>Rieder</surname><given-names>MJ</given-names></name><name><surname>Yi</surname><given-names>Q</given-names></name><name><surname>Kruglyak</surname><given-names>L</given-names></name><name><surname>Nickerson</surname><given-names>DA</given-names></name></person-group><article-title>Selecting a maximally informative set of single-nucleotide polymorphisms for association analysis using linkage disequilibrium.</article-title><source>Am J Hum Genet</source><year>2004</year><volume>74</volume><fpage>106</fpage><lpage>20</lpage><pub-id pub-id-type="pmid">14681826</pub-id></element-citation></ref><ref id="r37"><label>37</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Almasy</surname><given-names>L</given-names></name><name><surname>Blangero</surname><given-names>J</given-names></name></person-group><article-title>Multipoint quantitative-trait linkage analysis in general pedigrees.</article-title><source>Am J Hum Genet</source><year>1998</year><volume>62</volume><fpage>1198</fpage><lpage>211</lpage><pub-id pub-id-type="pmid">9545414</pub-id></element-citation></ref><ref id="r38"><label>38</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Fulker</surname><given-names>DW</given-names></name><name><surname>Cherny</surname><given-names>SS</given-names></name><name><surname>Cardon</surname><given-names>LR</given-names></name></person-group><article-title>Multipoint interval mapping of quantitative trait loci.</article-title><source>Am J Hum Genet</source><year>1995</year><volume>56</volume><fpage>1224</fpage><lpage>33</lpage><pub-id pub-id-type="pmid">7726180</pub-id></element-citation></ref><ref id="r39"><label>39</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kong</surname><given-names>A</given-names></name><name><surname>Gudbjartsson</surname><given-names>DF</given-names></name><name><surname>Sainz</surname><given-names>J</given-names></name><name><surname>Jonsdottir</surname><given-names>GM</given-names></name><name><surname>Gudjonsson</surname><given-names>SA</given-names></name><name><surname>Richardsson</surname><given-names>B</given-names></name><name><surname>Sigurdardottir</surname><given-names>S</given-names></name><name><surname>Barnard</surname><given-names>J</given-names></name><name><surname>Hallbeck</surname><given-names>B</given-names></name><name><surname>Masson</surname><given-names>G</given-names></name><name><surname>Shlien</surname><given-names>A</given-names></name><name><surname>Palsson</surname><given-names>ST</given-names></name><name><surname>Frigge</surname><given-names>ML</given-names></name><name><surname>Thorgeirsson</surname><given-names>TE</given-names></name><name><surname>Gulcher</surname><given-names>JR</given-names></name><name><surname>Stefansson</surname><given-names>K</given-names></name></person-group><article-title>A high-resolution recombination map of the human genome.</article-title><source>Nat Genet</source><year>2002</year><volume>31</volume><fpage>241</fpage><lpage>7</lpage><pub-id pub-id-type="pmid">12053178</pub-id></element-citation></ref><ref id="r40"><label>40</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Weeks</surname><given-names>DE</given-names></name><name><surname>Conley</surname><given-names>YP</given-names></name><name><surname>Mah</surname><given-names>TS</given-names></name><name><surname>Paul</surname><given-names>TO</given-names></name><name><surname>Morse</surname><given-names>L</given-names></name><name><surname>Ngo-Chang</surname><given-names>J</given-names></name><name><surname>Dailey</surname><given-names>JP</given-names></name><name><surname>Ferrell</surname><given-names>RE</given-names></name><name><surname>Gorin</surname><given-names>MB</given-names></name></person-group><article-title>A full genome scan for age-related maculopathy.</article-title><source>Hum Mol Genet</source><year>2000</year><volume>9</volume><fpage>1329</fpage><lpage>49</lpage><pub-id pub-id-type="pmid">10814715</pub-id></element-citation></ref><ref id="r41"><label>41</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Morton</surname><given-names>NE</given-names></name></person-group><article-title>Sequential tests for the detection of linkage.</article-title><source>Am J Hum Genet</source><year>1955</year><volume>7</volume><fpage>277</fpage><lpage>318</lpage><pub-id pub-id-type="pmid">13258560</pub-id></element-citation></ref></ref-list></back></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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