Evidence for novel susceptibility genes for late-onset Alzheimer's disease from a genome-wide association study of putative functional variants
Identifieur interne : 000F04 ( Main/Exploration ); précédent : 000F03; suivant : 000F05Evidence for novel susceptibility genes for late-onset Alzheimer's disease from a genome-wide association study of putative functional variants
Auteurs : Andrew Grupe [Royaume-Uni] ; Richard Abraham ; Yonghong Li ; Charles Rowland ; Paul Hollingworth ; Angharad Morgan ; Luke Jehu ; Ricardo Segurado ; David Stone ; Eric Schadt ; Maha Karnoub ; Petra Nowotny ; Kristina Tacey ; Joseph Catanese ; John Sninsky ; Carol Brayne ; David Rubinsztein ; Michael Gill ; Brian Lawlor ; Simon Lovestone ; Peter Holmans ; Michael O'Donovan ; John C. Morris ; Leon Thal ; Alison Goate ; Michael J. Owen ; Julie Williams [Royaume-Uni]Source :
- Human Molecular Genetics [ 0964-6906 ] ; 2007-04-15.
Abstract
This study sets out to identify novel susceptibility genes for late-onset Alzheimer's disease (LOAD) in a powerful set of samples from the UK and USA (1808 LOAD cases and 2062 controls). Allele frequencies of 17343 gene-based putative functional single nucleotide polymorphisms (SNPs) were tested for association with LOAD in a discovery casecontrol sample from the UK. A tiered strategy was used to follow-up significant variants from the discovery sample in four independent sample sets. Here, we report the identification of several candidate SNPs that show significant association with LOAD. Three of the identified markers are located on chromosome 19 (meta-analysis: full sample P 6.94E 81 to 0.0001), close to the APOE gene and exhibit linkage disequilibrium (LD) with the APOE4 and 2/3 variants (0.09 < D<1). Two of the three SNPs can be regarded as study-wide significant (expected number of false positives reaching the observed significance level less than 0.05 per study). Sixteen additional SNPs show evidence for association with LOAD [P 0.0010-0.00006; odds ratio (OR) 1.071.45], several of which map to known linkage regions, biological candidate genes and novel genes. Four SNPs not in LD with APOE show a false positive rate of less than 2 per study, one of which shows study-wide suggestive evidence taking account of 17343 tests. This is a missense mutation in the galanin-like peptide precursor gene (P 0.00005, OR 1.2, false positive rate 0.87).
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DOI: 10.1093/hmg/ddm031
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Grupe</name><affiliation><wicri:noCountry code="subField"></wicri:noCountry></affiliation><affiliation wicri:level="1"><country wicri:rule="url">Royaume-Uni</country></affiliation></author><author><name sortKey="Abraham, Richard" sort="Abraham, Richard" uniqKey="Abraham R" first="Richard" last="Abraham">Richard Abraham</name><affiliation><wicri:noCountry code="syntax">???</wicri:noCountry></affiliation></author><author><name sortKey="Li, Yonghong" sort="Li, Yonghong" uniqKey="Li Y" first="Yonghong" last="Li">Yonghong Li</name><affiliation><wicri:noCountry code="subField"></wicri:noCountry></affiliation></author><author><name sortKey="Rowland, Charles" sort="Rowland, Charles" uniqKey="Rowland C" first="Charles" last="Rowland">Charles Rowland</name><affiliation><wicri:noCountry code="subField"></wicri:noCountry></affiliation></author><author><name sortKey="Hollingworth, Paul" sort="Hollingworth, Paul" uniqKey="Hollingworth P" first="Paul" last="Hollingworth">Paul 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sortKey="Catanese, Joseph" sort="Catanese, Joseph" uniqKey="Catanese J" first="Joseph" last="Catanese">Joseph Catanese</name><affiliation><wicri:noCountry code="subField"></wicri:noCountry></affiliation></author><author><name sortKey="Sninsky, John" sort="Sninsky, John" uniqKey="Sninsky J" first="John" last="Sninsky">John Sninsky</name><affiliation><wicri:noCountry code="subField"></wicri:noCountry></affiliation></author><author><name sortKey="Brayne, Carol" sort="Brayne, Carol" uniqKey="Brayne C" first="Carol" last="Brayne">Carol Brayne</name><affiliation><wicri:noCountry code="syntax">???</wicri:noCountry></affiliation><affiliation><wicri:noCountry code="syntax">???</wicri:noCountry></affiliation></author><author><name sortKey="Rubinsztein, David" sort="Rubinsztein, David" uniqKey="Rubinsztein D" first="David" last="Rubinsztein">David Rubinsztein</name><affiliation><wicri:noCountry code="syntax">???</wicri:noCountry></affiliation><affiliation><wicri:noCountry code="syntax">???</wicri:noCountry></affiliation></author><author><name sortKey="Gill, Michael" sort="Gill, Michael" uniqKey="Gill M" first="Michael" last="Gill">Michael Gill</name><affiliation><wicri:noCountry code="syntax">???</wicri:noCountry></affiliation><affiliation><wicri:noCountry code="syntax">???</wicri:noCountry></affiliation></author><author><name sortKey="Lawlor, Brian" sort="Lawlor, Brian" uniqKey="Lawlor B" first="Brian" last="Lawlor">Brian Lawlor</name><affiliation><wicri:noCountry code="syntax">???</wicri:noCountry></affiliation><affiliation><wicri:noCountry code="syntax">???</wicri:noCountry></affiliation></author><author><name sortKey="Lovestone, Simon" sort="Lovestone, Simon" uniqKey="Lovestone S" first="Simon" last="Lovestone">Simon Lovestone</name><affiliation><wicri:noCountry code="syntax">???</wicri:noCountry></affiliation></author><author><name sortKey="Holmans, Peter" sort="Holmans, Peter" uniqKey="Holmans P" first="Peter" last="Holmans">Peter Holmans</name><affiliation><wicri:noCountry code="syntax">???</wicri:noCountry></affiliation></author><author><name sortKey="O Donovan, Michael" sort="O Donovan, Michael" uniqKey="O Donovan M" first="Michael" last="O'Donovan">Michael O'Donovan</name><affiliation><wicri:noCountry code="syntax">???</wicri:noCountry></affiliation></author><author><name sortKey="Morris, John C" sort="Morris, John C" uniqKey="Morris J" first="John C." last="Morris">John C. Morris</name><affiliation><wicri:noCountry code="syntax">???</wicri:noCountry></affiliation><affiliation><wicri:noCountry code="syntax">???</wicri:noCountry></affiliation><affiliation><wicri:noCountry code="subField"></wicri:noCountry></affiliation></author><author><name sortKey="Thal, Leon" sort="Thal, Leon" uniqKey="Thal L" first="Leon" last="Thal">Leon Thal</name><affiliation><wicri:noCountry code="syntax">???</wicri:noCountry></affiliation></author><author><name sortKey="Goate, Alison" sort="Goate, Alison" uniqKey="Goate A" first="Alison" last="Goate">Alison Goate</name><affiliation><wicri:noCountry code="syntax">???</wicri:noCountry></affiliation><affiliation><wicri:noCountry code="syntax">???</wicri:noCountry></affiliation><affiliation><wicri:noCountry code="subField"></wicri:noCountry></affiliation></author><author><name sortKey="Owen, Michael J" sort="Owen, Michael J" uniqKey="Owen M" first="Michael J." last="Owen">Michael J. Owen</name><affiliation><wicri:noCountry code="syntax">???</wicri:noCountry></affiliation></author><author><name sortKey="Williams, Julie" sort="Williams, Julie" uniqKey="Williams J" first="Julie" last="Williams">Julie Williams</name><affiliation><wicri:noCountry code="syntax">???</wicri:noCountry></affiliation><affiliation wicri:level="1"><country wicri:rule="url">Royaume-Uni</country></affiliation></author></analytic><monogr></monogr><series><title level="j">Human Molecular Genetics</title><idno type="ISSN">0964-6906</idno><idno type="eISSN">1460-2083</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2007-04-15">2007-04-15</date><biblScope unit="volume">16</biblScope><biblScope unit="issue">8</biblScope><biblScope unit="page" from="865">865</biblScope><biblScope unit="page" to="873">873</biblScope></imprint><idno type="ISSN">0964-6906</idno></series><idno type="istex">01A6A16E23F461E9BB300FB2080AD8F4B2CC9BE5</idno><idno type="DOI">10.1093/hmg/ddm031</idno><idno type="ArticleID">ddm031</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0964-6906</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract">This study sets out to identify novel susceptibility genes for late-onset Alzheimer's disease (LOAD) in a powerful set of samples from the UK and USA (1808 LOAD cases and 2062 controls). Allele frequencies of 17343 gene-based putative functional single nucleotide polymorphisms (SNPs) were tested for association with LOAD in a discovery casecontrol sample from the UK. A tiered strategy was used to follow-up significant variants from the discovery sample in four independent sample sets. Here, we report the identification of several candidate SNPs that show significant association with LOAD. Three of the identified markers are located on chromosome 19 (meta-analysis: full sample P 6.94E 81 to 0.0001), close to the APOE gene and exhibit linkage disequilibrium (LD) with the APOE4 and 2/3 variants (0.09 < D<1). Two of the three SNPs can be regarded as study-wide significant (expected number of false positives reaching the observed significance level less than 0.05 per study). Sixteen additional SNPs show evidence for association with LOAD [P 0.0010-0.00006; odds ratio (OR) 1.071.45], several of which map to known linkage regions, biological candidate genes and novel genes. Four SNPs not in LD with APOE show a false positive rate of less than 2 per study, one of which shows study-wide suggestive evidence taking account of 17343 tests. This is a missense mutation in the galanin-like peptide precursor gene (P 0.00005, OR 1.2, false positive rate 0.87).</div></front></TEI><affiliations><list><country><li>Royaume-Uni</li></country></list><tree><noCountry><name sortKey="Abraham, Richard" sort="Abraham, Richard" uniqKey="Abraham R" first="Richard" last="Abraham">Richard Abraham</name><name sortKey="Brayne, Carol" sort="Brayne, Carol" uniqKey="Brayne C" first="Carol" last="Brayne">Carol Brayne</name><name sortKey="Catanese, Joseph" sort="Catanese, Joseph" uniqKey="Catanese J" first="Joseph" last="Catanese">Joseph Catanese</name><name sortKey="Gill, Michael" sort="Gill, Michael" uniqKey="Gill M" first="Michael" last="Gill">Michael Gill</name><name sortKey="Goate, Alison" sort="Goate, Alison" uniqKey="Goate A" first="Alison" last="Goate">Alison Goate</name><name sortKey="Hollingworth, Paul" sort="Hollingworth, Paul" uniqKey="Hollingworth P" first="Paul" last="Hollingworth">Paul Hollingworth</name><name sortKey="Holmans, Peter" sort="Holmans, Peter" uniqKey="Holmans P" first="Peter" last="Holmans">Peter Holmans</name><name sortKey="Jehu, Luke" sort="Jehu, Luke" uniqKey="Jehu L" first="Luke" last="Jehu">Luke Jehu</name><name sortKey="Karnoub, Maha" sort="Karnoub, Maha" uniqKey="Karnoub M" first="Maha" last="Karnoub">Maha Karnoub</name><name sortKey="Lawlor, Brian" sort="Lawlor, Brian" uniqKey="Lawlor B" first="Brian" last="Lawlor">Brian Lawlor</name><name sortKey="Li, Yonghong" sort="Li, Yonghong" uniqKey="Li Y" first="Yonghong" last="Li">Yonghong Li</name><name sortKey="Lovestone, Simon" sort="Lovestone, Simon" uniqKey="Lovestone S" first="Simon" last="Lovestone">Simon Lovestone</name><name sortKey="Morgan, Angharad" sort="Morgan, Angharad" uniqKey="Morgan A" first="Angharad" last="Morgan">Angharad Morgan</name><name sortKey="Morris, John C" sort="Morris, John C" uniqKey="Morris J" first="John C." last="Morris">John C. Morris</name><name sortKey="Nowotny, Petra" sort="Nowotny, Petra" uniqKey="Nowotny P" first="Petra" last="Nowotny">Petra Nowotny</name><name sortKey="O Donovan, Michael" sort="O Donovan, Michael" uniqKey="O Donovan M" first="Michael" last="O'Donovan">Michael O'Donovan</name><name sortKey="Owen, Michael J" sort="Owen, Michael J" uniqKey="Owen M" first="Michael J." last="Owen">Michael J. Owen</name><name sortKey="Rowland, Charles" sort="Rowland, Charles" uniqKey="Rowland C" first="Charles" last="Rowland">Charles Rowland</name><name sortKey="Rubinsztein, David" sort="Rubinsztein, David" uniqKey="Rubinsztein D" first="David" last="Rubinsztein">David Rubinsztein</name><name sortKey="Schadt, Eric" sort="Schadt, Eric" uniqKey="Schadt E" first="Eric" last="Schadt">Eric Schadt</name><name sortKey="Segurado, Ricardo" sort="Segurado, Ricardo" uniqKey="Segurado R" first="Ricardo" last="Segurado">Ricardo Segurado</name><name sortKey="Sninsky, John" sort="Sninsky, John" uniqKey="Sninsky J" first="John" last="Sninsky">John Sninsky</name><name sortKey="Stone, David" sort="Stone, David" uniqKey="Stone D" first="David" last="Stone">David Stone</name><name sortKey="Tacey, Kristina" sort="Tacey, Kristina" uniqKey="Tacey K" first="Kristina" last="Tacey">Kristina Tacey</name><name sortKey="Thal, Leon" sort="Thal, Leon" uniqKey="Thal L" first="Leon" last="Thal">Leon Thal</name></noCountry><country name="Royaume-Uni"><noRegion><name sortKey="Grupe, Andrew" sort="Grupe, Andrew" uniqKey="Grupe A" first="Andrew" last="Grupe">Andrew Grupe</name></noRegion><name sortKey="Williams, Julie" sort="Williams, Julie" uniqKey="Williams J" first="Julie" last="Williams">Julie Williams</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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