Integrated genome-wide association, coexpression network, and expression single nucleotide polymorphism analysis identifies novel pathway in allergic rhinitis
Identifieur interne : 001508 ( Pmc/Checkpoint ); précédent : 001507; suivant : 001509Integrated genome-wide association, coexpression network, and expression single nucleotide polymorphism analysis identifies novel pathway in allergic rhinitis
Auteurs : Supinda Bunyavanich [États-Unis] ; Eric E. Schadt [États-Unis] ; Blanca E. Himes [États-Unis] ; Jessica Lasky-Su [États-Unis] ; Weiliang Qiu [États-Unis] ; Ross Lazarus [États-Unis, Australie] ; John P. Ziniti [États-Unis] ; Ariella Cohain [États-Unis] ; Michael Linderman [États-Unis] ; Dara G. Torgerson [États-Unis] ; Celeste S. Eng [États-Unis] ; Maria Pino-Yanes [États-Unis, Espagne] ; Badri Padhukasahasram [États-Unis] ; James J. Yang [États-Unis] ; Rasika A. Mathias [États-Unis] ; Terri H. Beaty [États-Unis] ; Xingnan Li [États-Unis] ; Penelope Graves [États-Unis] ; Isabelle Romieu [France] ; Blanca Del Rio Navarro [Mexique] ; M Towhid Salam [États-Unis] ; Hita Vora [États-Unis] ; Dan L. Nicolae [États-Unis] ; Carole Ober [États-Unis] ; Fernando D. Martinez [États-Unis] ; Eugene R. Bleecker [États-Unis] ; Deborah A. Meyers [États-Unis] ; W James Gauderman [États-Unis] ; Frank Gilliland [États-Unis] ; Esteban G. Burchard [États-Unis] ; Kathleen C. Barnes [États-Unis] ; L Keoki Williams [États-Unis] ; Stephanie J. London [États-Unis] ; Bin Zhang [États-Unis] ; Benjamin A. Raby [États-Unis] ; Scott T. Weiss [États-Unis]Source :
- BMC Medical Genomics [ 1755-8794 ] ; 2014.
Abstract
Allergic rhinitis is a common disease whose genetic basis is incompletely explained. We report an integrated genomic analysis of allergic rhinitis.
We performed genome wide association studies (GWAS) of allergic rhinitis in 5633 ethnically diverse North American subjects. Next, we profiled gene expression in disease-relevant tissue (peripheral blood CD4+ lymphocytes) collected from subjects who had been genotyped. We then integrated the GWAS and gene expression data using expression single nucleotide (eSNP), coexpression network, and pathway approaches to identify the biologic relevance of our GWAS.
GWAS revealed ethnicity-specific findings, with 4 genome-wide significant loci among Latinos and 1 genome-wide significant locus in the GWAS meta-analysis across ethnic groups. To identify biologic context for these results, we constructed a coexpression network to define modules of genes with similar patterns of CD4+ gene expression (coexpression modules) that could serve as constructs of broader gene expression. 6 of the 22 GWAS loci with P-value ≤ 1x10−6 tagged one particular coexpression module (4.0-fold enrichment, P-value 0.0029), and this module also had the greatest enrichment (3.4-fold enrichment, P-value 2.6 × 10−24) for allergic rhinitis-associated eSNPs (genetic variants associated with both gene expression and allergic rhinitis). The integrated GWAS, coexpression network, and eSNP results therefore supported this coexpression module as an allergic rhinitis module. Pathway analysis revealed that the module was enriched for mitochondrial pathways (8.6-fold enrichment, P-value 4.5 × 10−72).
Our results highlight mitochondrial pathways as a target for further investigation of allergic rhinitis mechanism and treatment. Our integrated approach can be applied to provide biologic context for GWAS of other diseases.
Url:
DOI: 10.1186/1755-8794-7-48
PubMed: 25085501
PubMed Central: 4127082
Affiliations:
- Australie, Espagne, France, Mexique, États-Unis
- Arizona, Auvergne-Rhône-Alpes, Californie, Caroline du Nord, Communauté de Madrid, Illinois, Maryland, Massachusetts, Michigan, Rhône-Alpes, Victoria (État), État de New York
- Los Angeles, Lyon, Madrid, Melbourne
- Université de Californie du Sud
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<author><name sortKey="Pino Yanes, Maria" sort="Pino Yanes, Maria" uniqKey="Pino Yanes M" first="Maria" last="Pino-Yanes">Maria Pino-Yanes</name>
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<affiliation wicri:level="3"><nlm:aff id="I5">IBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain</nlm:aff>
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<author><name sortKey="Yang, James J" sort="Yang, James J" uniqKey="Yang J" first="James J" last="Yang">James J. Yang</name>
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<author><name sortKey="Li, Xingnan" sort="Li, Xingnan" uniqKey="Li X" first="Xingnan" last="Li">Xingnan Li</name>
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<author><name sortKey="Graves, Penelope" sort="Graves, Penelope" uniqKey="Graves P" first="Penelope" last="Graves">Penelope Graves</name>
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<wicri:regionArea>Arizona Respiratory Center and BIO5 Institute, University of Arizona, Tucson, AZ</wicri:regionArea>
<placeName><region type="state">Arizona</region>
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</affiliation>
</author>
<author><name sortKey="Romieu, Isabelle" sort="Romieu, Isabelle" uniqKey="Romieu I" first="Isabelle" last="Romieu">Isabelle Romieu</name>
<affiliation wicri:level="3"><nlm:aff id="I11">International Agency for Research on Cancer, Lyon, France</nlm:aff>
<country xml:lang="fr">France</country>
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<author><name sortKey="Navarro, Blanca Del Rio" sort="Navarro, Blanca Del Rio" uniqKey="Navarro B" first="Blanca Del Rio" last="Navarro">Blanca Del Rio Navarro</name>
<affiliation wicri:level="1"><nlm:aff id="I12">Hospital Infantil Federico Gómez, México City, Mexico</nlm:aff>
<country xml:lang="fr">Mexique</country>
<wicri:regionArea>Hospital Infantil Federico Gómez, México City</wicri:regionArea>
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<author><name sortKey="Salam, M Towhid" sort="Salam, M Towhid" uniqKey="Salam M" first="M Towhid" last="Salam">M Towhid Salam</name>
<affiliation wicri:level="4"><nlm:aff id="I13">Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Preventive Medicine, University of Southern California, Los Angeles, CA</wicri:regionArea>
<placeName><region type="state">Californie</region>
<settlement type="city">Los Angeles</settlement>
</placeName>
<orgName type="university">Université de Californie du Sud</orgName>
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<author><name sortKey="Vora, Hita" sort="Vora, Hita" uniqKey="Vora H" first="Hita" last="Vora">Hita Vora</name>
<affiliation wicri:level="4"><nlm:aff id="I13">Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Preventive Medicine, University of Southern California, Los Angeles, CA</wicri:regionArea>
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<settlement type="city">Los Angeles</settlement>
</placeName>
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<author><name sortKey="Nicolae, Dan L" sort="Nicolae, Dan L" uniqKey="Nicolae D" first="Dan L" last="Nicolae">Dan L. Nicolae</name>
<affiliation wicri:level="2"><nlm:aff id="I14">Department of Human Genetics, University of Chicago, Chicago, IL, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Human Genetics, University of Chicago, Chicago, IL</wicri:regionArea>
<placeName><region type="state">Illinois</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Ober, Carole" sort="Ober, Carole" uniqKey="Ober C" first="Carole" last="Ober">Carole Ober</name>
<affiliation wicri:level="2"><nlm:aff id="I14">Department of Human Genetics, University of Chicago, Chicago, IL, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Human Genetics, University of Chicago, Chicago, IL</wicri:regionArea>
<placeName><region type="state">Illinois</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Martinez, Fernando D" sort="Martinez, Fernando D" uniqKey="Martinez F" first="Fernando D" last="Martinez">Fernando D. Martinez</name>
<affiliation wicri:level="2"><nlm:aff id="I10">Arizona Respiratory Center and BIO5 Institute, University of Arizona, Tucson, AZ, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Arizona Respiratory Center and BIO5 Institute, University of Arizona, Tucson, AZ</wicri:regionArea>
<placeName><region type="state">Arizona</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Bleecker, Eugene R" sort="Bleecker, Eugene R" uniqKey="Bleecker E" first="Eugene R" last="Bleecker">Eugene R. Bleecker</name>
<affiliation wicri:level="2"><nlm:aff id="I9">Center for Genomics, Wake Forest University School of Medicine, Winston Salem, NC, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Genomics, Wake Forest University School of Medicine, Winston Salem, NC</wicri:regionArea>
<placeName><region type="state">Caroline du Nord</region>
</placeName>
</affiliation>
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<author><name sortKey="Meyers, Deborah A" sort="Meyers, Deborah A" uniqKey="Meyers D" first="Deborah A" last="Meyers">Deborah A. Meyers</name>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Genomics, Wake Forest University School of Medicine, Winston Salem, NC</wicri:regionArea>
<placeName><region type="state">Caroline du Nord</region>
</placeName>
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<author><name sortKey="Gauderman, W James" sort="Gauderman, W James" uniqKey="Gauderman W" first="W James" last="Gauderman">W James Gauderman</name>
<affiliation wicri:level="4"><nlm:aff id="I13">Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA</nlm:aff>
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<wicri:regionArea>Department of Preventive Medicine, University of Southern California, Los Angeles, CA</wicri:regionArea>
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<settlement type="city">Los Angeles</settlement>
</placeName>
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<author><name sortKey="Gilliland, Frank" sort="Gilliland, Frank" uniqKey="Gilliland F" first="Frank" last="Gilliland">Frank Gilliland</name>
<affiliation wicri:level="4"><nlm:aff id="I13">Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Preventive Medicine, University of Southern California, Los Angeles, CA</wicri:regionArea>
<placeName><region type="state">Californie</region>
<settlement type="city">Los Angeles</settlement>
</placeName>
<orgName type="university">Université de Californie du Sud</orgName>
</affiliation>
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<author><name sortKey="Burchard, Esteban G" sort="Burchard, Esteban G" uniqKey="Burchard E" first="Esteban G" last="Burchard">Esteban G. Burchard</name>
<affiliation wicri:level="2"><nlm:aff id="I4">Department of Medicine and Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Medicine and Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Barnes, Kathleen C" sort="Barnes, Kathleen C" uniqKey="Barnes K" first="Kathleen C" last="Barnes">Kathleen C. Barnes</name>
<affiliation wicri:level="2"><nlm:aff id="I8">Departments of Medicine and Epidemiology, Johns Hopkins University, Baltimore, MD, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Departments of Medicine and Epidemiology, Johns Hopkins University, Baltimore, MD</wicri:regionArea>
<placeName><region type="state">Maryland</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Williams, L Keoki" sort="Williams, L Keoki" uniqKey="Williams L" first="L Keoki" last="Williams">L Keoki Williams</name>
<affiliation wicri:level="2"><nlm:aff id="I6">Center for Health Policy and Health Services Research, Henry Ford Health System, Detroit, MI, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Health Policy and Health Services Research, Henry Ford Health System, Detroit, MI</wicri:regionArea>
<placeName><region type="state">Michigan</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="I15">Department of Internal Medicine, Henry Ford Health System, Detroit, MI, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Internal Medicine, Henry Ford Health System, Detroit, MI</wicri:regionArea>
<placeName><region type="state">Michigan</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="London, Stephanie J" sort="London, Stephanie J" uniqKey="London S" first="Stephanie J" last="London">Stephanie J. London</name>
<affiliation wicri:level="2"><nlm:aff id="I16">Division of Intramural Research, Department of Health and Human Services, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle, Park, NC, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Intramural Research, Department of Health and Human Services, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle, Park, NC</wicri:regionArea>
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</affiliation>
</author>
<author><name sortKey="Zhang, Bin" sort="Zhang, Bin" uniqKey="Zhang B" first="Bin" last="Zhang">Bin Zhang</name>
<affiliation wicri:level="2"><nlm:aff id="I1">Department of Genetics and Genomic Sciences and Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, 10029 New York, NY, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Genetics and Genomic Sciences and Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, 10029 New York, NY</wicri:regionArea>
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</affiliation>
</author>
<author><name sortKey="Raby, Benjamin A" sort="Raby, Benjamin A" uniqKey="Raby B" first="Benjamin A" last="Raby">Benjamin A. Raby</name>
<affiliation wicri:level="2"><nlm:aff id="I3">Channing Division of Network Medicine, Department of Medicine, Brigham & Women’s Hospital and Harvard Medical School, Boston, MA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Channing Division of Network Medicine, Department of Medicine, Brigham & Women’s Hospital and Harvard Medical School, Boston, MA</wicri:regionArea>
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</placeName>
</affiliation>
</author>
<author><name sortKey="Weiss, Scott T" sort="Weiss, Scott T" uniqKey="Weiss S" first="Scott T" last="Weiss">Scott T. Weiss</name>
<affiliation wicri:level="2"><nlm:aff id="I3">Channing Division of Network Medicine, Department of Medicine, Brigham & Women’s Hospital and Harvard Medical School, Boston, MA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Channing Division of Network Medicine, Department of Medicine, Brigham & Women’s Hospital and Harvard Medical School, Boston, MA</wicri:regionArea>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Integrated genome-wide association, coexpression network, and expression single nucleotide polymorphism analysis identifies novel pathway in allergic rhinitis</title>
<author><name sortKey="Bunyavanich, Supinda" sort="Bunyavanich, Supinda" uniqKey="Bunyavanich S" first="Supinda" last="Bunyavanich">Supinda Bunyavanich</name>
<affiliation wicri:level="2"><nlm:aff id="I1">Department of Genetics and Genomic Sciences and Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, 10029 New York, NY, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Genetics and Genomic Sciences and Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, 10029 New York, NY</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="I2">Division of Pediatric Allergy and Immunology, Department of Pediatrics, and Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Pediatric Allergy and Immunology, Department of Pediatrics, and Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Schadt, Eric E" sort="Schadt, Eric E" uniqKey="Schadt E" first="Eric E" last="Schadt">Eric E. Schadt</name>
<affiliation wicri:level="2"><nlm:aff id="I1">Department of Genetics and Genomic Sciences and Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, 10029 New York, NY, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Genetics and Genomic Sciences and Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, 10029 New York, NY</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Himes, Blanca E" sort="Himes, Blanca E" uniqKey="Himes B" first="Blanca E" last="Himes">Blanca E. Himes</name>
<affiliation wicri:level="2"><nlm:aff id="I3">Channing Division of Network Medicine, Department of Medicine, Brigham & Women’s Hospital and Harvard Medical School, Boston, MA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Channing Division of Network Medicine, Department of Medicine, Brigham & Women’s Hospital and Harvard Medical School, Boston, MA</wicri:regionArea>
<placeName><region type="state">Massachusetts</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Lasky Su, Jessica" sort="Lasky Su, Jessica" uniqKey="Lasky Su J" first="Jessica" last="Lasky-Su">Jessica Lasky-Su</name>
<affiliation wicri:level="2"><nlm:aff id="I3">Channing Division of Network Medicine, Department of Medicine, Brigham & Women’s Hospital and Harvard Medical School, Boston, MA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Channing Division of Network Medicine, Department of Medicine, Brigham & Women’s Hospital and Harvard Medical School, Boston, MA</wicri:regionArea>
<placeName><region type="state">Massachusetts</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Qiu, Weiliang" sort="Qiu, Weiliang" uniqKey="Qiu W" first="Weiliang" last="Qiu">Weiliang Qiu</name>
<affiliation wicri:level="2"><nlm:aff id="I3">Channing Division of Network Medicine, Department of Medicine, Brigham & Women’s Hospital and Harvard Medical School, Boston, MA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Channing Division of Network Medicine, Department of Medicine, Brigham & Women’s Hospital and Harvard Medical School, Boston, MA</wicri:regionArea>
<placeName><region type="state">Massachusetts</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Lazarus, Ross" sort="Lazarus, Ross" uniqKey="Lazarus R" first="Ross" last="Lazarus">Ross Lazarus</name>
<affiliation wicri:level="2"><nlm:aff id="I3">Channing Division of Network Medicine, Department of Medicine, Brigham & Women’s Hospital and Harvard Medical School, Boston, MA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Channing Division of Network Medicine, Department of Medicine, Brigham & Women’s Hospital and Harvard Medical School, Boston, MA</wicri:regionArea>
<placeName><region type="state">Massachusetts</region>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="I17">Medical Bioinformatics, Baker IDI, Melbourne, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Medical Bioinformatics, Baker IDI, Melbourne</wicri:regionArea>
<placeName><settlement type="city">Melbourne</settlement>
<region type="état">Victoria (État)</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Ziniti, John P" sort="Ziniti, John P" uniqKey="Ziniti J" first="John P" last="Ziniti">John P. Ziniti</name>
<affiliation wicri:level="2"><nlm:aff id="I3">Channing Division of Network Medicine, Department of Medicine, Brigham & Women’s Hospital and Harvard Medical School, Boston, MA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Channing Division of Network Medicine, Department of Medicine, Brigham & Women’s Hospital and Harvard Medical School, Boston, MA</wicri:regionArea>
<placeName><region type="state">Massachusetts</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Cohain, Ariella" sort="Cohain, Ariella" uniqKey="Cohain A" first="Ariella" last="Cohain">Ariella Cohain</name>
<affiliation wicri:level="2"><nlm:aff id="I1">Department of Genetics and Genomic Sciences and Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, 10029 New York, NY, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Genetics and Genomic Sciences and Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, 10029 New York, NY</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Linderman, Michael" sort="Linderman, Michael" uniqKey="Linderman M" first="Michael" last="Linderman">Michael Linderman</name>
<affiliation wicri:level="2"><nlm:aff id="I1">Department of Genetics and Genomic Sciences and Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, 10029 New York, NY, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Genetics and Genomic Sciences and Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, 10029 New York, NY</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Torgerson, Dara G" sort="Torgerson, Dara G" uniqKey="Torgerson D" first="Dara G" last="Torgerson">Dara G. Torgerson</name>
<affiliation wicri:level="2"><nlm:aff id="I4">Department of Medicine and Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Medicine and Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Eng, Celeste S" sort="Eng, Celeste S" uniqKey="Eng C" first="Celeste S" last="Eng">Celeste S. Eng</name>
<affiliation wicri:level="2"><nlm:aff id="I4">Department of Medicine and Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Medicine and Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Pino Yanes, Maria" sort="Pino Yanes, Maria" uniqKey="Pino Yanes M" first="Maria" last="Pino-Yanes">Maria Pino-Yanes</name>
<affiliation wicri:level="2"><nlm:aff id="I4">Department of Medicine and Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Medicine and Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="I5">IBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain</nlm:aff>
<country xml:lang="fr">Espagne</country>
<wicri:regionArea>IBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid</wicri:regionArea>
<placeName><settlement type="city">Madrid</settlement>
<region nuts="2" type="region">Communauté de Madrid</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Padhukasahasram, Badri" sort="Padhukasahasram, Badri" uniqKey="Padhukasahasram B" first="Badri" last="Padhukasahasram">Badri Padhukasahasram</name>
<affiliation wicri:level="2"><nlm:aff id="I6">Center for Health Policy and Health Services Research, Henry Ford Health System, Detroit, MI, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Health Policy and Health Services Research, Henry Ford Health System, Detroit, MI</wicri:regionArea>
<placeName><region type="state">Michigan</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Yang, James J" sort="Yang, James J" uniqKey="Yang J" first="James J" last="Yang">James J. Yang</name>
<affiliation wicri:level="2"><nlm:aff id="I7">Department of Public Health Sciences, Henry Ford Health System, Detroit, MI, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Public Health Sciences, Henry Ford Health System, Detroit, MI</wicri:regionArea>
<placeName><region type="state">Michigan</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Mathias, Rasika A" sort="Mathias, Rasika A" uniqKey="Mathias R" first="Rasika A" last="Mathias">Rasika A. Mathias</name>
<affiliation wicri:level="2"><nlm:aff id="I8">Departments of Medicine and Epidemiology, Johns Hopkins University, Baltimore, MD, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Departments of Medicine and Epidemiology, Johns Hopkins University, Baltimore, MD</wicri:regionArea>
<placeName><region type="state">Maryland</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Beaty, Terri H" sort="Beaty, Terri H" uniqKey="Beaty T" first="Terri H" last="Beaty">Terri H. Beaty</name>
<affiliation wicri:level="2"><nlm:aff id="I8">Departments of Medicine and Epidemiology, Johns Hopkins University, Baltimore, MD, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Departments of Medicine and Epidemiology, Johns Hopkins University, Baltimore, MD</wicri:regionArea>
<placeName><region type="state">Maryland</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Li, Xingnan" sort="Li, Xingnan" uniqKey="Li X" first="Xingnan" last="Li">Xingnan Li</name>
<affiliation wicri:level="2"><nlm:aff id="I9">Center for Genomics, Wake Forest University School of Medicine, Winston Salem, NC, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Genomics, Wake Forest University School of Medicine, Winston Salem, NC</wicri:regionArea>
<placeName><region type="state">Caroline du Nord</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Graves, Penelope" sort="Graves, Penelope" uniqKey="Graves P" first="Penelope" last="Graves">Penelope Graves</name>
<affiliation wicri:level="2"><nlm:aff id="I10">Arizona Respiratory Center and BIO5 Institute, University of Arizona, Tucson, AZ, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Arizona Respiratory Center and BIO5 Institute, University of Arizona, Tucson, AZ</wicri:regionArea>
<placeName><region type="state">Arizona</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Romieu, Isabelle" sort="Romieu, Isabelle" uniqKey="Romieu I" first="Isabelle" last="Romieu">Isabelle Romieu</name>
<affiliation wicri:level="3"><nlm:aff id="I11">International Agency for Research on Cancer, Lyon, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>International Agency for Research on Cancer, Lyon</wicri:regionArea>
<placeName><region type="region">Auvergne-Rhône-Alpes</region>
<region type="old region">Rhône-Alpes</region>
<settlement type="city">Lyon</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Navarro, Blanca Del Rio" sort="Navarro, Blanca Del Rio" uniqKey="Navarro B" first="Blanca Del Rio" last="Navarro">Blanca Del Rio Navarro</name>
<affiliation wicri:level="1"><nlm:aff id="I12">Hospital Infantil Federico Gómez, México City, Mexico</nlm:aff>
<country xml:lang="fr">Mexique</country>
<wicri:regionArea>Hospital Infantil Federico Gómez, México City</wicri:regionArea>
<wicri:noRegion>México City</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Salam, M Towhid" sort="Salam, M Towhid" uniqKey="Salam M" first="M Towhid" last="Salam">M Towhid Salam</name>
<affiliation wicri:level="4"><nlm:aff id="I13">Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Preventive Medicine, University of Southern California, Los Angeles, CA</wicri:regionArea>
<placeName><region type="state">Californie</region>
<settlement type="city">Los Angeles</settlement>
</placeName>
<orgName type="university">Université de Californie du Sud</orgName>
</affiliation>
</author>
<author><name sortKey="Vora, Hita" sort="Vora, Hita" uniqKey="Vora H" first="Hita" last="Vora">Hita Vora</name>
<affiliation wicri:level="4"><nlm:aff id="I13">Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Preventive Medicine, University of Southern California, Los Angeles, CA</wicri:regionArea>
<placeName><region type="state">Californie</region>
<settlement type="city">Los Angeles</settlement>
</placeName>
<orgName type="university">Université de Californie du Sud</orgName>
</affiliation>
</author>
<author><name sortKey="Nicolae, Dan L" sort="Nicolae, Dan L" uniqKey="Nicolae D" first="Dan L" last="Nicolae">Dan L. Nicolae</name>
<affiliation wicri:level="2"><nlm:aff id="I14">Department of Human Genetics, University of Chicago, Chicago, IL, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Human Genetics, University of Chicago, Chicago, IL</wicri:regionArea>
<placeName><region type="state">Illinois</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Ober, Carole" sort="Ober, Carole" uniqKey="Ober C" first="Carole" last="Ober">Carole Ober</name>
<affiliation wicri:level="2"><nlm:aff id="I14">Department of Human Genetics, University of Chicago, Chicago, IL, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Human Genetics, University of Chicago, Chicago, IL</wicri:regionArea>
<placeName><region type="state">Illinois</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Martinez, Fernando D" sort="Martinez, Fernando D" uniqKey="Martinez F" first="Fernando D" last="Martinez">Fernando D. Martinez</name>
<affiliation wicri:level="2"><nlm:aff id="I10">Arizona Respiratory Center and BIO5 Institute, University of Arizona, Tucson, AZ, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Arizona Respiratory Center and BIO5 Institute, University of Arizona, Tucson, AZ</wicri:regionArea>
<placeName><region type="state">Arizona</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Bleecker, Eugene R" sort="Bleecker, Eugene R" uniqKey="Bleecker E" first="Eugene R" last="Bleecker">Eugene R. Bleecker</name>
<affiliation wicri:level="2"><nlm:aff id="I9">Center for Genomics, Wake Forest University School of Medicine, Winston Salem, NC, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Genomics, Wake Forest University School of Medicine, Winston Salem, NC</wicri:regionArea>
<placeName><region type="state">Caroline du Nord</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Meyers, Deborah A" sort="Meyers, Deborah A" uniqKey="Meyers D" first="Deborah A" last="Meyers">Deborah A. Meyers</name>
<affiliation wicri:level="2"><nlm:aff id="I9">Center for Genomics, Wake Forest University School of Medicine, Winston Salem, NC, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Genomics, Wake Forest University School of Medicine, Winston Salem, NC</wicri:regionArea>
<placeName><region type="state">Caroline du Nord</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Gauderman, W James" sort="Gauderman, W James" uniqKey="Gauderman W" first="W James" last="Gauderman">W James Gauderman</name>
<affiliation wicri:level="4"><nlm:aff id="I13">Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Preventive Medicine, University of Southern California, Los Angeles, CA</wicri:regionArea>
<placeName><region type="state">Californie</region>
<settlement type="city">Los Angeles</settlement>
</placeName>
<orgName type="university">Université de Californie du Sud</orgName>
</affiliation>
</author>
<author><name sortKey="Gilliland, Frank" sort="Gilliland, Frank" uniqKey="Gilliland F" first="Frank" last="Gilliland">Frank Gilliland</name>
<affiliation wicri:level="4"><nlm:aff id="I13">Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Preventive Medicine, University of Southern California, Los Angeles, CA</wicri:regionArea>
<placeName><region type="state">Californie</region>
<settlement type="city">Los Angeles</settlement>
</placeName>
<orgName type="university">Université de Californie du Sud</orgName>
</affiliation>
</author>
<author><name sortKey="Burchard, Esteban G" sort="Burchard, Esteban G" uniqKey="Burchard E" first="Esteban G" last="Burchard">Esteban G. Burchard</name>
<affiliation wicri:level="2"><nlm:aff id="I4">Department of Medicine and Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Medicine and Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Barnes, Kathleen C" sort="Barnes, Kathleen C" uniqKey="Barnes K" first="Kathleen C" last="Barnes">Kathleen C. Barnes</name>
<affiliation wicri:level="2"><nlm:aff id="I8">Departments of Medicine and Epidemiology, Johns Hopkins University, Baltimore, MD, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Departments of Medicine and Epidemiology, Johns Hopkins University, Baltimore, MD</wicri:regionArea>
<placeName><region type="state">Maryland</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Williams, L Keoki" sort="Williams, L Keoki" uniqKey="Williams L" first="L Keoki" last="Williams">L Keoki Williams</name>
<affiliation wicri:level="2"><nlm:aff id="I6">Center for Health Policy and Health Services Research, Henry Ford Health System, Detroit, MI, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Health Policy and Health Services Research, Henry Ford Health System, Detroit, MI</wicri:regionArea>
<placeName><region type="state">Michigan</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="I15">Department of Internal Medicine, Henry Ford Health System, Detroit, MI, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Internal Medicine, Henry Ford Health System, Detroit, MI</wicri:regionArea>
<placeName><region type="state">Michigan</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="London, Stephanie J" sort="London, Stephanie J" uniqKey="London S" first="Stephanie J" last="London">Stephanie J. London</name>
<affiliation wicri:level="2"><nlm:aff id="I16">Division of Intramural Research, Department of Health and Human Services, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle, Park, NC, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Intramural Research, Department of Health and Human Services, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle, Park, NC</wicri:regionArea>
<placeName><region type="state">Caroline du Nord</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Zhang, Bin" sort="Zhang, Bin" uniqKey="Zhang B" first="Bin" last="Zhang">Bin Zhang</name>
<affiliation wicri:level="2"><nlm:aff id="I1">Department of Genetics and Genomic Sciences and Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, 10029 New York, NY, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Genetics and Genomic Sciences and Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, 10029 New York, NY</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Raby, Benjamin A" sort="Raby, Benjamin A" uniqKey="Raby B" first="Benjamin A" last="Raby">Benjamin A. Raby</name>
<affiliation wicri:level="2"><nlm:aff id="I3">Channing Division of Network Medicine, Department of Medicine, Brigham & Women’s Hospital and Harvard Medical School, Boston, MA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Channing Division of Network Medicine, Department of Medicine, Brigham & Women’s Hospital and Harvard Medical School, Boston, MA</wicri:regionArea>
<placeName><region type="state">Massachusetts</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Weiss, Scott T" sort="Weiss, Scott T" uniqKey="Weiss S" first="Scott T" last="Weiss">Scott T. Weiss</name>
<affiliation wicri:level="2"><nlm:aff id="I3">Channing Division of Network Medicine, Department of Medicine, Brigham & Women’s Hospital and Harvard Medical School, Boston, MA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Channing Division of Network Medicine, Department of Medicine, Brigham & Women’s Hospital and Harvard Medical School, Boston, MA</wicri:regionArea>
<placeName><region type="state">Massachusetts</region>
</placeName>
</affiliation>
</author>
</analytic>
<series><title level="j">BMC Medical Genomics</title>
<idno type="eISSN">1755-8794</idno>
<imprint><date when="2014">2014</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><sec><title>Background</title>
<p>Allergic rhinitis is a common disease whose genetic basis is incompletely explained. We report an integrated genomic analysis of allergic rhinitis.</p>
</sec>
<sec><title>Methods</title>
<p>We performed genome wide association studies (GWAS) of allergic rhinitis in 5633 ethnically diverse North American subjects. Next, we profiled gene expression in disease-relevant tissue (peripheral blood CD4+ lymphocytes) collected from subjects who had been genotyped. We then integrated the GWAS and gene expression data using expression single nucleotide (eSNP), coexpression network, and pathway approaches to identify the biologic relevance of our GWAS.</p>
</sec>
<sec><title>Results</title>
<p>GWAS revealed ethnicity-specific findings, with 4 genome-wide significant loci among Latinos and 1 genome-wide significant locus in the GWAS meta-analysis across ethnic groups. To identify biologic context for these results, we constructed a coexpression network to define modules of genes with similar patterns of CD4+ gene expression (coexpression modules) that could serve as constructs of broader gene expression. 6 of the 22 GWAS loci with P-value ≤ 1x10<sup>−6</sup>
tagged one particular coexpression module (4.0-fold enrichment, P-value 0.0029), and this module also had the greatest enrichment (3.4-fold enrichment, P-value 2.6 × 10<sup>−24</sup>
) for allergic rhinitis-associated eSNPs (genetic variants associated with both gene expression and allergic rhinitis). The integrated GWAS, coexpression network, and eSNP results therefore supported this coexpression module as an allergic rhinitis module. Pathway analysis revealed that the module was enriched for mitochondrial pathways (8.6-fold enrichment, P-value 4.5 × 10<sup>−72</sup>
).</p>
</sec>
<sec><title>Conclusions</title>
<p>Our results highlight mitochondrial pathways as a target for further investigation of allergic rhinitis mechanism and treatment. Our integrated approach can be applied to provide biologic context for GWAS of other diseases.</p>
</sec>
</div>
</front>
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<front><journal-meta><journal-id journal-id-type="nlm-ta">BMC Med Genomics</journal-id>
<journal-id journal-id-type="iso-abbrev">BMC Med Genomics</journal-id>
<journal-title-group><journal-title>BMC Medical Genomics</journal-title>
</journal-title-group>
<issn pub-type="epub">1755-8794</issn>
<publisher><publisher-name>BioMed Central</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">25085501</article-id>
<article-id pub-id-type="pmc">4127082</article-id>
<article-id pub-id-type="publisher-id">1755-8794-7-48</article-id>
<article-id pub-id-type="doi">10.1186/1755-8794-7-48</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>Integrated genome-wide association, coexpression network, and expression single nucleotide polymorphism analysis identifies novel pathway in allergic rhinitis</article-title>
</title-group>
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<aff id="I1"><label>1</label>
Department of Genetics and Genomic Sciences and Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, 10029 New York, NY, USA</aff>
<aff id="I2"><label>2</label>
Division of Pediatric Allergy and Immunology, Department of Pediatrics, and Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA</aff>
<aff id="I3"><label>3</label>
Channing Division of Network Medicine, Department of Medicine, Brigham & Women’s Hospital and Harvard Medical School, Boston, MA, USA</aff>
<aff id="I4"><label>4</label>
Department of Medicine and Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA</aff>
<aff id="I5"><label>5</label>
IBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain</aff>
<aff id="I6"><label>6</label>
Center for Health Policy and Health Services Research, Henry Ford Health System, Detroit, MI, USA</aff>
<aff id="I7"><label>7</label>
Department of Public Health Sciences, Henry Ford Health System, Detroit, MI, USA</aff>
<aff id="I8"><label>8</label>
Departments of Medicine and Epidemiology, Johns Hopkins University, Baltimore, MD, USA</aff>
<aff id="I9"><label>9</label>
Center for Genomics, Wake Forest University School of Medicine, Winston Salem, NC, USA</aff>
<aff id="I10"><label>10</label>
Arizona Respiratory Center and BIO5 Institute, University of Arizona, Tucson, AZ, USA</aff>
<aff id="I11"><label>11</label>
International Agency for Research on Cancer, Lyon, France</aff>
<aff id="I12"><label>12</label>
Hospital Infantil Federico Gómez, México City, Mexico</aff>
<aff id="I13"><label>13</label>
Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA</aff>
<aff id="I14"><label>14</label>
Department of Human Genetics, University of Chicago, Chicago, IL, USA</aff>
<aff id="I15"><label>15</label>
Department of Internal Medicine, Henry Ford Health System, Detroit, MI, USA</aff>
<aff id="I16"><label>16</label>
Division of Intramural Research, Department of Health and Human Services, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle, Park, NC, USA</aff>
<aff id="I17"><label>17</label>
Medical Bioinformatics, Baker IDI, Melbourne, Australia</aff>
<pub-date pub-type="collection"><year>2014</year>
</pub-date>
<pub-date pub-type="epub"><day>2</day>
<month>8</month>
<year>2014</year>
</pub-date>
<volume>7</volume>
<fpage>48</fpage>
<lpage>48</lpage>
<history><date date-type="received"><day>3</day>
<month>1</month>
<year>2014</year>
</date>
<date date-type="accepted"><day>4</day>
<month>6</month>
<year>2014</year>
</date>
</history>
<permissions><copyright-statement>Copyright © 2014 Bunyavanich et al.; licensee BioMed Central Ltd.</copyright-statement>
<copyright-year>2014</copyright-year>
<copyright-holder>Bunyavanich et al.; licensee BioMed Central Ltd.</copyright-holder>
<license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/2.0"><license-p>This is an Open Access article distributed under the terms of the Creative Commons Attribution License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/2.0">http://creativecommons.org/licenses/by/2.0</ext-link>
), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/publicdomain/zero/1.0/">http://creativecommons.org/publicdomain/zero/1.0/</ext-link>
) applies to the data made available in this article, unless otherwise stated.</license-p>
</license>
</permissions>
<self-uri xlink:href="http://www.biomedcentral.com/1755-8794/7/48"></self-uri>
<abstract><sec><title>Background</title>
<p>Allergic rhinitis is a common disease whose genetic basis is incompletely explained. We report an integrated genomic analysis of allergic rhinitis.</p>
</sec>
<sec><title>Methods</title>
<p>We performed genome wide association studies (GWAS) of allergic rhinitis in 5633 ethnically diverse North American subjects. Next, we profiled gene expression in disease-relevant tissue (peripheral blood CD4+ lymphocytes) collected from subjects who had been genotyped. We then integrated the GWAS and gene expression data using expression single nucleotide (eSNP), coexpression network, and pathway approaches to identify the biologic relevance of our GWAS.</p>
</sec>
<sec><title>Results</title>
<p>GWAS revealed ethnicity-specific findings, with 4 genome-wide significant loci among Latinos and 1 genome-wide significant locus in the GWAS meta-analysis across ethnic groups. To identify biologic context for these results, we constructed a coexpression network to define modules of genes with similar patterns of CD4+ gene expression (coexpression modules) that could serve as constructs of broader gene expression. 6 of the 22 GWAS loci with P-value ≤ 1x10<sup>−6</sup>
tagged one particular coexpression module (4.0-fold enrichment, P-value 0.0029), and this module also had the greatest enrichment (3.4-fold enrichment, P-value 2.6 × 10<sup>−24</sup>
) for allergic rhinitis-associated eSNPs (genetic variants associated with both gene expression and allergic rhinitis). The integrated GWAS, coexpression network, and eSNP results therefore supported this coexpression module as an allergic rhinitis module. Pathway analysis revealed that the module was enriched for mitochondrial pathways (8.6-fold enrichment, P-value 4.5 × 10<sup>−72</sup>
).</p>
</sec>
<sec><title>Conclusions</title>
<p>Our results highlight mitochondrial pathways as a target for further investigation of allergic rhinitis mechanism and treatment. Our integrated approach can be applied to provide biologic context for GWAS of other diseases.</p>
</sec>
</abstract>
<kwd-group><kwd>Genome-wide association study</kwd>
<kwd>Allergic rhinitis</kwd>
<kwd>Coexpression network</kwd>
<kwd>Expression single-nucleotide polymorphism</kwd>
<kwd>Coexpression module</kwd>
<kwd>Pathway</kwd>
<kwd>Mitochondria</kwd>
<kwd>Hay fever</kwd>
<kwd>Allergy</kwd>
</kwd-group>
</article-meta>
</front>
</pmc>
<affiliations><list><country><li>Australie</li>
<li>Espagne</li>
<li>France</li>
<li>Mexique</li>
<li>États-Unis</li>
</country>
<region><li>Arizona</li>
<li>Auvergne-Rhône-Alpes</li>
<li>Californie</li>
<li>Caroline du Nord</li>
<li>Communauté de Madrid</li>
<li>Illinois</li>
<li>Maryland</li>
<li>Massachusetts</li>
<li>Michigan</li>
<li>Rhône-Alpes</li>
<li>Victoria (État)</li>
<li>État de New York</li>
</region>
<settlement><li>Los Angeles</li>
<li>Lyon</li>
<li>Madrid</li>
<li>Melbourne</li>
</settlement>
<orgName><li>Université de Californie du Sud</li>
</orgName>
</list>
<tree><country name="États-Unis"><region name="État de New York"><name sortKey="Bunyavanich, Supinda" sort="Bunyavanich, Supinda" uniqKey="Bunyavanich S" first="Supinda" last="Bunyavanich">Supinda Bunyavanich</name>
</region>
<name sortKey="Barnes, Kathleen C" sort="Barnes, Kathleen C" uniqKey="Barnes K" first="Kathleen C" last="Barnes">Kathleen C. Barnes</name>
<name sortKey="Beaty, Terri H" sort="Beaty, Terri H" uniqKey="Beaty T" first="Terri H" last="Beaty">Terri H. Beaty</name>
<name sortKey="Bleecker, Eugene R" sort="Bleecker, Eugene R" uniqKey="Bleecker E" first="Eugene R" last="Bleecker">Eugene R. Bleecker</name>
<name sortKey="Bunyavanich, Supinda" sort="Bunyavanich, Supinda" uniqKey="Bunyavanich S" first="Supinda" last="Bunyavanich">Supinda Bunyavanich</name>
<name sortKey="Burchard, Esteban G" sort="Burchard, Esteban G" uniqKey="Burchard E" first="Esteban G" last="Burchard">Esteban G. Burchard</name>
<name sortKey="Cohain, Ariella" sort="Cohain, Ariella" uniqKey="Cohain A" first="Ariella" last="Cohain">Ariella Cohain</name>
<name sortKey="Eng, Celeste S" sort="Eng, Celeste S" uniqKey="Eng C" first="Celeste S" last="Eng">Celeste S. Eng</name>
<name sortKey="Gauderman, W James" sort="Gauderman, W James" uniqKey="Gauderman W" first="W James" last="Gauderman">W James Gauderman</name>
<name sortKey="Gilliland, Frank" sort="Gilliland, Frank" uniqKey="Gilliland F" first="Frank" last="Gilliland">Frank Gilliland</name>
<name sortKey="Graves, Penelope" sort="Graves, Penelope" uniqKey="Graves P" first="Penelope" last="Graves">Penelope Graves</name>
<name sortKey="Himes, Blanca E" sort="Himes, Blanca E" uniqKey="Himes B" first="Blanca E" last="Himes">Blanca E. Himes</name>
<name sortKey="Lasky Su, Jessica" sort="Lasky Su, Jessica" uniqKey="Lasky Su J" first="Jessica" last="Lasky-Su">Jessica Lasky-Su</name>
<name sortKey="Lazarus, Ross" sort="Lazarus, Ross" uniqKey="Lazarus R" first="Ross" last="Lazarus">Ross Lazarus</name>
<name sortKey="Li, Xingnan" sort="Li, Xingnan" uniqKey="Li X" first="Xingnan" last="Li">Xingnan Li</name>
<name sortKey="Linderman, Michael" sort="Linderman, Michael" uniqKey="Linderman M" first="Michael" last="Linderman">Michael Linderman</name>
<name sortKey="London, Stephanie J" sort="London, Stephanie J" uniqKey="London S" first="Stephanie J" last="London">Stephanie J. London</name>
<name sortKey="Martinez, Fernando D" sort="Martinez, Fernando D" uniqKey="Martinez F" first="Fernando D" last="Martinez">Fernando D. Martinez</name>
<name sortKey="Mathias, Rasika A" sort="Mathias, Rasika A" uniqKey="Mathias R" first="Rasika A" last="Mathias">Rasika A. Mathias</name>
<name sortKey="Meyers, Deborah A" sort="Meyers, Deborah A" uniqKey="Meyers D" first="Deborah A" last="Meyers">Deborah A. Meyers</name>
<name sortKey="Nicolae, Dan L" sort="Nicolae, Dan L" uniqKey="Nicolae D" first="Dan L" last="Nicolae">Dan L. Nicolae</name>
<name sortKey="Ober, Carole" sort="Ober, Carole" uniqKey="Ober C" first="Carole" last="Ober">Carole Ober</name>
<name sortKey="Padhukasahasram, Badri" sort="Padhukasahasram, Badri" uniqKey="Padhukasahasram B" first="Badri" last="Padhukasahasram">Badri Padhukasahasram</name>
<name sortKey="Pino Yanes, Maria" sort="Pino Yanes, Maria" uniqKey="Pino Yanes M" first="Maria" last="Pino-Yanes">Maria Pino-Yanes</name>
<name sortKey="Qiu, Weiliang" sort="Qiu, Weiliang" uniqKey="Qiu W" first="Weiliang" last="Qiu">Weiliang Qiu</name>
<name sortKey="Raby, Benjamin A" sort="Raby, Benjamin A" uniqKey="Raby B" first="Benjamin A" last="Raby">Benjamin A. Raby</name>
<name sortKey="Salam, M Towhid" sort="Salam, M Towhid" uniqKey="Salam M" first="M Towhid" last="Salam">M Towhid Salam</name>
<name sortKey="Schadt, Eric E" sort="Schadt, Eric E" uniqKey="Schadt E" first="Eric E" last="Schadt">Eric E. Schadt</name>
<name sortKey="Torgerson, Dara G" sort="Torgerson, Dara G" uniqKey="Torgerson D" first="Dara G" last="Torgerson">Dara G. Torgerson</name>
<name sortKey="Vora, Hita" sort="Vora, Hita" uniqKey="Vora H" first="Hita" last="Vora">Hita Vora</name>
<name sortKey="Weiss, Scott T" sort="Weiss, Scott T" uniqKey="Weiss S" first="Scott T" last="Weiss">Scott T. Weiss</name>
<name sortKey="Williams, L Keoki" sort="Williams, L Keoki" uniqKey="Williams L" first="L Keoki" last="Williams">L Keoki Williams</name>
<name sortKey="Williams, L Keoki" sort="Williams, L Keoki" uniqKey="Williams L" first="L Keoki" last="Williams">L Keoki Williams</name>
<name sortKey="Yang, James J" sort="Yang, James J" uniqKey="Yang J" first="James J" last="Yang">James J. Yang</name>
<name sortKey="Zhang, Bin" sort="Zhang, Bin" uniqKey="Zhang B" first="Bin" last="Zhang">Bin Zhang</name>
<name sortKey="Ziniti, John P" sort="Ziniti, John P" uniqKey="Ziniti J" first="John P" last="Ziniti">John P. Ziniti</name>
</country>
<country name="Australie"><region name="Victoria (État)"><name sortKey="Lazarus, Ross" sort="Lazarus, Ross" uniqKey="Lazarus R" first="Ross" last="Lazarus">Ross Lazarus</name>
</region>
</country>
<country name="Espagne"><region name="Communauté de Madrid"><name sortKey="Pino Yanes, Maria" sort="Pino Yanes, Maria" uniqKey="Pino Yanes M" first="Maria" last="Pino-Yanes">Maria Pino-Yanes</name>
</region>
</country>
<country name="France"><region name="Auvergne-Rhône-Alpes"><name sortKey="Romieu, Isabelle" sort="Romieu, Isabelle" uniqKey="Romieu I" first="Isabelle" last="Romieu">Isabelle Romieu</name>
</region>
</country>
<country name="Mexique"><noRegion><name sortKey="Navarro, Blanca Del Rio" sort="Navarro, Blanca Del Rio" uniqKey="Navarro B" first="Blanca Del Rio" last="Navarro">Blanca Del Rio Navarro</name>
</noRegion>
</country>
</tree>
</affiliations>
</record>
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