A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.
Lars G FritscheWilmar IglJessica N Cooke BaileyFelix GrassmannSebanti SenguptaJennifer L Bragg-GreshamKathryn P BurdonScott J HebbringCindy WenMathias GorskiIvana K KimDavid ChoDonald ZackEric SouiedHendrik P N SchollElisa BalaKristine E LeeDavid J HunterRebecca J SardellPaul MitchellJoanna E MerriamValentina CiprianiJoshua D HoffmanTina SchickYara T E LechanteurRobyn H GuymerMatthew P JohnsonYingda JiangChloe M StantonGabriëlle H S BuitendijkXiaowei ZhanAlan M KwongAlexis BoledaMatthew BrooksLinn GieserRinki RatnapriyaKari E BranhamJohanna R FoersterJohn R HeckenlivelyMohammad I OthmanBrendan J VoteHelena Hai LiangEmmanuelle SouzeauIan L McAllisterTimothy IsaacsJanette HallStewart LakeDavid A MackeyIan J ConstableJamie E CraigTerrie E KitchnerZhenglin YangZhiguang SuHongrong LuoDaniel ChenHong OuyangKen FlaggDanni LinGuanping MaoHenry FerreyraKlaus StarkClaudia N von StrachwitzArmin WolfCaroline BrandlGuenther RudolphMatthias OldenMargaux A MorrisonDenise J MorganMatthew SchuJeeyun AhnGiuliana SilvestriEvangelia E TsironiKyu Hyung ParkLindsay A FarrerAnton OrlinAlexander BruckerMingyao LiChristine A CurcioSaddek Mohand-SaïdJosé-Alain SahelIsabelle AudoMustapha BenchabouneAngela J CreeChristina A RennieSrinivas V GoverdhanMichelle GruninShira Hagbi-LeviPeter CampochiaroNicholas KatsanisFrank G HolzFrédéric BlondHélène BlanchéJean-François DeleuzeRobert P IgoBarbara TruittNeal S PeacheyStacy M MeuerChelsea E MyersEmily L MooreRonald KleinMichael A HauserEric A PostelMonique D CourtenayStephen G SchwartzJaclyn L KovachWilliam K ScottGerald LiewAva G TanBamini GopinathJohn C MerriamR Theodore SmithJane C KhanHumma ShahidAnthony T MooreJ Allie McGrathReneé LauxMilam A BrantleyAnita AgarwalLebriz ErsoyAlbert CaramoyThomas LangmannNicole T M SaksensEiko K de JongCarel B HoyngMelinda S CainAndrea J RichardsonTammy M MartinJohn BlangeroDaniel E WeeksBal DhillonCornelia M van DuijnKimberly F DohenyJane RommCaroline C W KlaverCaroline HaywardMichael B GorinMichael L KleinPaul N BairdAnneke I den HollanderSascha FauserJohn R W YatesRando AllikmetsJie Jin WangDebra A SchaumbergBarbara E K KleinStephanie A HagstromItay ChowersAndrew J LoteryThierry LéveillardKang ZhangMurray H BrilliantAlex W HewittAnand SwaroopEmily Y ChewMargaret A Pericak-VanceMargaret DeAngelisDwight StambolianJonathan L HainesSudha K IyengarBernhard H F WeberGonçalo R AbecasisIris M HeidPublished in: Nature genetics (2015)
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.