A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants

被引：1165

作者：

Fritsche, Lars G. ^{[1
]}

Igl, Wilmar ^{[2
]}

Bailey, Jessica N. Cooke ^{[3
]}

Grassmann, Felix ^{[4
]}

Sengupta, Sebanti ^{[1
]}

Bragg-Gresham, Jennifer L. ^{[1
,5
]}

Burdon, Kathryn P. ^{[6
]}

Hebbring, Scott J. ^{[7
]}

Wen, Cindy ^{[8
,9
]}

Gorski, Mathias ^{[2
]}

Kim, Ivana K. ^{[10
]}

Cho, David ^{[11
]}

Zack, Donald ^{[12
,13
,14
,15
,16
]}

Souied, Eric ^{[17
]}

Scholl, Hendrik P. N. ^{[12
,18
]}

Bala, Elisa ^{[19
]}

Lee, Kristine E. ^{[20
]}

Hunter, David J. ^{[21
,22
]}

Sardell, Rebecca J. ^{[23
]}

Mitchell, Paul ^{[24
]}

Merriam, Joanna E. ^{[25
]}

Cipriani, Valentina ^{[26
,27
]}

Hoffman, Joshua D. ^{[28
]}

Schick, Tina ^{[29
]}

Lechanteur, Yara T. E. ^{[30
]}

Guymer, Robyn H. ^{[31
]}

Johnson, Matthew P. ^{[32
]}

Jiang, Yingda ^{[33
]}

Stanton, Chloe M. ^{[34
]}

Buitendijk, Gabrielle H. S. ^{[35
,36
]}

Zhan, Xiaowei ^{[1
,37
,38
]}

Kwong, Alan M. ^{[1
]}

Boleda, Alexis ^{[39
]}

Brooks, Matthew ^{[39
]}

Gieser, Linn ^{[39
]}

Ratnapriya, Rinki ^{[39
]}

Branham, Kari E. ^{[40
]}

Foerster, Johanna R. ^{[1
]}

Heckenlively, John R. ^{[40
]}

Othman, Mohammad I. ^{[40
]}

Vote, Brendan J. ^{[6
]}

Liang, Helena Hai ^{[31
]}

Souzeau, Emmanuelle ^{[41
]}

McAllister, Ian L. ^{[42
]}

Isaacs, Timothy ^{[42
]}

Hall, Janette ^{[41
]}

Lake, Stewart ^{[41
]}

Mackey, David A. ^{[6
,31
,42
]}

Constable, Ian J. ^{[42
]}

Craig, Jamie E. ^{[41
]}

机构：

[1] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA

[2] Univ Regensburg, Dept Genet Epidemiol, D-93053 Regensburg, Germany

[3] Case Western Reserve Univ, Sch Med, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA

[4] Univ Regensburg, Inst Human Genet, D-93053 Regensburg, Germany

[5] Univ Michigan, Dept Internal Med Nephrol, Kidney Epidemiol & Cost Ctr, Ann Arbor, MI 48109 USA

[6] Univ Tasmania, Menzies Res Inst Tasmania, Sch Med, Hobart, Tas, Australia

[7] Marshfield Clin Res Fdn, Ctr Human Genet, Marshfield, WI USA

[8] Univ Calif San Diego, Dept Ophthalmol, San Diego, CA 92103 USA

[9] Vet Affairs San Diego Hlth Syst, La Jolla, CA USA

[10] Harvard Univ, Sch Med, Dept Ophthalmol, Retina Serv,Massachusetts Eye & Ear, Boston, MA USA

[11] Univ Penn, Dept Ophthalmol, Perelman Sch Med, Philadelphia, PA 19104 USA

[12] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Dept Ophthalmol, Baltimore, MD 21205 USA

[13] Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA

[14] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA

[15] Johns Hopkins Univ, Sch Med, Inst Genet Med, Baltimore, MD USA

[16] Univ Paris 06, Inst Vis, Paris, France

[17] Univ Paris Est Creteil, Hop Henri Mondor, Hop Intercommunal Creteil, Creteil, France

[18] Univ Bonn, Dept Ophthalmol, Bonn, Germany

[19] Louis Stokes Cleveland Vet Affairs Med Ctr, Cleveland, OH USA

[20] Univ Wisconsin, Dept Ophthalmol & Visual Sci, Madison, WI USA

[21] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA

[22] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA

[23] Univ Miami, Miller Sch Med, John P Hussman Inst Human Genom, Miami, FL 33136 USA

[24] Univ Sydney, Dept Ophthalmol, Ctr Vis Res, Sydney, NSW 2006, Australia

[25] CUNY, Dept Ophthalmol, New York, NY 10021 USA

[26] UCL, Inst Ophthalmol, London, England

[27] Moorfields Eye Hosp, London, England

[28] Vanderbilt Univ, Med Ctr, Ctr Human Genet Res, Nashville, TN USA

[29] Univ Hosp Cologne, Dept Ophthalmol, Cologne, Germany

[30] Radboud Univ Nijmegen, Med Ctr, Dept Ophthalmol, NL-6525 ED Nijmegen, Netherlands

[31] Univ Melbourne, Royal Victorian Eye & Ear Hosp, Ctr Eye Res Australia, East Melbourne, Vic, Australia

[32] Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, Brownsville, TX USA

[33] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA

[34] Univ Edinburgh, Inst Genet & Mol Med, MRC, Human Genet Unit, Edinburgh, Midlothian, Scotland

[35] Erasmus MC, Dept Ophthalmol, Rotterdam, Netherlands

[36] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands

[37] Univ Texas SW Med Ctr Dallas, Dept Clin Sci, Quantitat Biomed Res Ctr, Dallas, TX 75390 USA

[38] Univ Texas SW Med Ctr Dallas, Ctr Genet Host Def, Dallas, TX 75390 USA

[39] NEI, N NRL, US Natl Inst Hlth, Bethesda, MD USA

[40] Univ Michigan, Kellogg Eye Ctr, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48109 USA

[41] Flinders Univ S Australia, Flinders Med Ctr, Dept Ophthalmol, Adelaide, SA 5001, Australia

[42] Univ Western Australia, Lions Eye Inst, Ctr Ophthalmol & Visual Sci, Perth, WA 6009, Australia

[43] Hosp Univ Elect Sci & Technol China, Sichuan Prov Key Lab Human Dis Gene Study, Chengdu, Peoples R China

[44] Sichuan Prov Peoples Hosp, Chengdu, Peoples R China

[45] Chinese Acad Sci, Sichuan Translat Med Hosp, Chengdu, Peoples R China

[46] Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Mol Med Res Ctr, Chengdu 610064, Peoples R China

[47] EyeCte Southwest, Stuttgart, Germany

[48] Univ Munich, Univ Eye Clin, Munich, Germany

[49] Univ Hosp Regensburg, Dept Ophthalmol, Regensburg, Germany

[50] Univ Utah, Dept Ophthalmol & Visual Sci, Salt Lake City, UT USA

来源：

NATURE GENETICS | 2016年 / 48卷 / 02期

关键词：

SEQUENCING IDENTIFIES RARE; BODY-MASS INDEX; HIGH-RISK; SUSCEPTIBILITY LOCI; DISEASE; GENE; MUTATION; BIOLOGY; OSTEOARTHRITIS; METAANALYSIS;

D O I：

10.1038/ng.3448

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 x 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 x 10(-10)). Very rare coding variants (frequency <0.1 %) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.

引用

页码：134 / 143

页数：10

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