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

Publication ,  Journal Article
Fritsche, LG; Igl, W; Bailey, JNC; Grassmann, F; Sengupta, S; Bragg-Gresham, JL; Burdon, KP; Hebbring, SJ; Wen, C; Gorski, M; Kim, IK; Cho, D ...
Published in: Nat Genet
February 2016

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 × 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 × 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.

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Published In

Nat Genet

DOI

EISSN

1546-1718

Publication Date

February 2016

Volume

48

Issue

2

Start / End Page

134 / 143

Location

United States

Related Subject Headings

  • Mutation
  • Macular Degeneration
  • Humans
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease
  • Developmental Biology
  • 3105 Genetics
  • 3102 Bioinformatics and computational biology
  • 3001 Agricultural biotechnology
  • 11 Medical and Health Sciences
 

Citation

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Fritsche, L. G., Igl, W., Bailey, J. N. C., Grassmann, F., Sengupta, S., Bragg-Gresham, J. L., … Heid, I. M. (2016). A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants. Nat Genet, 48(2), 134–143. https://doi.org/10.1038/ng.3448
Fritsche, Lars G., Wilmar Igl, Jessica N Cooke Bailey, Felix Grassmann, Sebanti Sengupta, Jennifer L. Bragg-Gresham, Kathryn P. Burdon, et al. “A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.Nat Genet 48, no. 2 (February 2016): 134–43. https://doi.org/10.1038/ng.3448.
Fritsche LG, Igl W, Bailey JNC, Grassmann F, Sengupta S, Bragg-Gresham JL, et al. A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants. Nat Genet. 2016 Feb;48(2):134–43.
Fritsche, Lars G., et al. “A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.Nat Genet, vol. 48, no. 2, Feb. 2016, pp. 134–43. Pubmed, doi:10.1038/ng.3448.
Fritsche LG, Igl W, Bailey JNC, Grassmann F, Sengupta S, Bragg-Gresham JL, Burdon KP, Hebbring SJ, Wen C, Gorski M, Kim IK, Cho D, Zack D, Souied E, Scholl HPN, Bala E, Lee KE, Hunter DJ, Sardell RJ, Mitchell P, Merriam JE, Cipriani V, Hoffman JD, Schick T, Lechanteur YTE, Guymer RH, Johnson MP, Jiang Y, Stanton CM, Buitendijk GHS, Zhan X, Kwong AM, Boleda A, Brooks M, Gieser L, Ratnapriya R, Branham KE, Foerster JR, Heckenlively JR, Othman MI, Vote BJ, Liang HH, Souzeau E, McAllister IL, Isaacs T, Hall J, Lake S, Mackey DA, Constable IJ, Craig JE, Kitchner TE, Yang Z, Su Z, Luo H, Chen D, Ouyang H, Flagg K, Lin D, Mao G, Ferreyra H, Stark K, von Strachwitz CN, Wolf A, Brandl C, Rudolph G, Olden M, Morrison MA, Morgan DJ, Schu M, Ahn J, Silvestri G, Tsironi EE, Park KH, Farrer LA, Orlin A, Brucker A, Li M, Curcio CA, Mohand-Saïd S, Sahel J-A, Audo I, Benchaboune M, Cree AJ, Rennie CA, Goverdhan SV, Grunin M, Hagbi-Levi S, Campochiaro P, Katsanis N, Holz FG, Blond F, Blanché H, Deleuze J-F, Igo RP, Truitt B, Peachey NS, Meuer SM, Myers CE, Moore EL, Klein R, Hauser MA, Postel EA, Courtenay MD, Schwartz SG, Kovach JL, Scott WK, Liew G, Tan AG, Gopinath B, Merriam JC, Smith RT, Khan JC, Shahid H, Moore AT, McGrath JA, Laux R, Brantley MA, Agarwal A, Ersoy L, Caramoy A, Langmann T, Saksens NTM, de Jong EK, Hoyng CB, Cain MS, Richardson AJ, Martin TM, Blangero J, Weeks DE, Dhillon B, van Duijn CM, Doheny KF, Romm J, Klaver CCW, Hayward C, Gorin MB, Klein ML, Baird PN, den Hollander AI, Fauser S, Yates JRW, Allikmets R, Wang JJ, Schaumberg DA, Klein BEK, Hagstrom SA, Chowers I, Lotery AJ, Léveillard T, Zhang K, Brilliant MH, Hewitt AW, Swaroop A, Chew EY, Pericak-Vance MA, DeAngelis M, Stambolian D, Haines JL, Iyengar SK, Weber BHF, Abecasis GR, Heid IM. A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants. Nat Genet. 2016 Feb;48(2):134–143.

Published In

Nat Genet

DOI

EISSN

1546-1718

Publication Date

February 2016

Volume

48

Issue

2

Start / End Page

134 / 143

Location

United States

Related Subject Headings

  • Mutation
  • Macular Degeneration
  • Humans
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease
  • Developmental Biology
  • 3105 Genetics
  • 3102 Bioinformatics and computational biology
  • 3001 Agricultural biotechnology
  • 11 Medical and Health Sciences