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

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  • Lars G Fritsche
  • Wilmar Igl
  • Jessica N Cooke Bailey
  • Felix Grassmann
  • Sebanti Sengupta
  • Jennifer L Bragg-Gresham
  • Kathryn P Burdon
  • Scott J Hebbring
  • Cindy Wen
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  • Joanna E Merriam
  • Valentina Cipriani
  • Joshua D Hoffman
  • Tina Schick
  • Yara T E Lechanteur
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  • Matthew P Johnson
  • Yingda Jiang
  • Gabriëlle H S Buitendijk
  • Xiaowei Zhan
  • Alan M Kwong
  • Alexis Boleda
  • Matthew Brooks
  • Linn Gieser
  • Rinki Ratnapriya
  • Kari E Branham
  • Johanna R Foerster
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  • Mohammad I Othman
  • Brendan J Vote
  • Helena Hai Liang
  • Emmanuelle Souzeau
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  • Stewart Lake
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  • Terrie E Kitchner
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  • Zhiguang Su
  • Hongrong Luo
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  • Hong Ouyang
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  • Guenther Rudolph
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  • Giuliana Silvestri
  • Evangelia E Tsironi
  • Kyu Hyung Park
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  • Jane C Khan
  • Humma Shahid
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  • Reneé Laux
  • Milam A Brantley
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  • Debra A Schaumberg
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  • Stephanie A Hagstrom
  • Itay Chowers
  • Andrew J Lotery
  • Thierry Léveillard
  • Kang Zhang
  • Murray H Brilliant
  • Alex W Hewitt
  • Anand Swaroop
  • Emily Y Chew
  • Margaret A Pericak-Vance
  • Margaret DeAngelis
  • Dwight Stambolian
  • Jonathan L Haines
  • Sudha K Iyengar
  • Bernhard H F Weber
  • Gonçalo R Abecasis
  • Iris M Heid

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http://www.nature.com/ng/journal/v48/n2/full/ng.3448.html
Original languageEnglish
Pages (from-to)134
Number of pages143
JournalNature Genetics
DOIs
Publication statusPublished - 21 Dec 2015

Abstract

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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