Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci.
Tin AungMineo OzakiMei Chin LeeUrsula Schlötzer-SchrehardtGudmar ThorleifssonTakanori MizoguchiRobert P IgoAravind HaripriyaSusan E WilliamsYury S AstakhovAndrew C OrrKathryn P BurdonSatoko NakanoKazuhiko MoriKhaled Abu-AmeroMichael A HauserZheng LiGopalakrishnan PrakadeeswariJessica N Cooke BaileyAlina Popa CherecheanuJae Hee KangSarah C NelsonKen HayashiShin-Ichi ManabeShigeyasu KazamaTomasz ZarnowskiKenji InoueMurat IrkecMiguel Coca-PradosKazuhisa SugiyamaIrma JärveläPatricio SchlottmannS Fabian LernerHasnaa LamariYildirim NilgünMukharram M BikbovKi Ho ParkSoon Cheol ChaKenji YamashiroJuan C ZentenoJost Bruno JonasRajesh S KumarShamira A PereraAnita S Y ChanNino KobakhidzeRonnie GeorgeLingam VijayaTan DoDeepak P EdwardLourdes de Juan MarcosMohammad PakravanSasan MoghimiRyuichi IdetaDaniella Bach-HolmPer KappelgaardBarbara WirostkoSamuel ThomasDaniel GastonKaren BedardWenda L GreerZhenglin YangXueyi ChenLulin HuangJinghong SangHongyan JiaLiyun JiaChunyan QiaoHui ZhangXuyang LiuBowen ZhaoYa-Xing WangLiang XuStéphanie LeruezPascal ReynierGeorge ChichuaSergo TabagariSteffen UebeMatthias ZenkelDaniel BernerGeorg MossböckNicole WeisschuhUrsula HojaUlrich-Christoph Welge-LuessenChristian MardinPanayiota FountiAnthi ChatzikyriakidouTheofanis PappasEleftherios AnastasopoulosAlexandros LambropoulosArkasubhra GhoshRohit ShettyNatalia PorporatoVijayan SaravananRengaraj VenkateshChandrashekaran ShivkumarNarendran KalpanaSripriya SarangapaniMozhgan R KanaviAfsaneh Naderi BeniShahin YazdaniAlireza LashayHoma NaderifarNassim KhatibiAntonio FeaCarlo LaviaLaura DallortoTeresa RollePaolo FrezzottiDaniela PaoliErika SalviPaolo ManuntaYosai MoriKazunori MiyataTomomi HigashideEtsuo ChiharaSatoshi IshikoAkitoshi YoshidaMasahide YanagiYoshiaki KiuchiTsutomu OhashiToshiya SakuraiTakako SugimotoHideki ChumanMakoto AiharaMasaru InataniMasahiro MiyakeNorimoto GotohFumihiko MatsudaNagahisa YoshimuraYoko IkedaMorio UenoChie SotozonoJin Wook JeoungMin SagongKyu Hyung ParkJeeyun AhnMarisa Cruz-AguilarSidi M EzzouhairiAbderrahman RafeiYaan Fun ChongXiao Yu NgShuang Ru GohYueming ChenVictor H K YongMuhammad Imran KhanOlusola O OlawoyeAdeyinka O AshayeIdakwo UgbedeAdeola OnakoyaNkiru Kizor-AkaraiweChaiwat TeekhasaeneeYanin SuwanWasu SupakontanasanSuhanya OkekeNkechi J UcheIfeoma AsimaduHumaira AyubFarah AkhtarEwa Kosior-JareckaUrszula LukasikIgnacio LischinskyVania CastroRodolfo Perez GrossmannGordana Sunaric MegevandSylvain RoyEdward DervanEoin SilkeAparna RaoPriti SahayPablo ForneroOsvaldo CuelloDelia SivoriTamara ZompaRichard A MillsEmmanuelle SouzeauPaul MitchellJie Jin WangAlex W HewittMichael CooteJonathan G CrowstonSergei Y AstakhovEugeny L AkopovAnton EmelyanovVera VysochinskayaGyulli M KazakbaevaRinat FayzrakhmanovSaleh A Al-ObeidanOhoud OwaidhahLeyla Ali AljasimBalram ChowbayJia-Nee FooRaphael Q SohKar-Seng SimZhicheng XieAugustine W O CheongShi Qi MokHui Meng SooXiao Yin ChenSu Qin PehKhai Koon HengRahat HusainSu-Ling HoAxel Maximilian HillmerChing-Yu ChengFrancisco A Escudero-DomínguezRogelio González-SarmientoFederico M TorresAntonio SalasKessara PathanapitoonLinda HansapinyoBoonsong WanichwecharugruangNaris KitnarongAnavaj SakuntabhaiHip X NguynGiang T T NguynTrình V NguynWerner ZenzAlexander BinderDaniela S KlobassaMartin L HibberdSonia DavilaStefan HermsMarkus M NöthenSusanne MoebusRobyn M RautenbachAri ZiskindTrevor R CarmichaelMichele RamsayLydia ÁlvarezMontserrat GarcíaHéctor González-IglesiasPedro P Rodríguez-CalvoLuis Fernández-Vega CuetoÇilingir OguzNevbahar TamcelikEray AtalayBilge BatuDilek AktasBurcu KasımM Roy WilsonAnne L ColemanYutao LiuPratap ChallaLeon HerndonRachel W KuchteyJohn KuchteyKaren CurtinCraig J ChayaAlan CrandallLinda M ZangwillTien Yin WongMasakazu NakanoShigeru KinoshitaAnneke I den HollanderEija VestiJohn H FingertRichard K LeeArthur J SitBradford J ShingletonNingli WangDaniele CusiRaheel QamarPeter KraftMargaret A Pericak-VanceSoumya RaychaudhuriSteffen HeegaardTero KiveläAndré ReisFriedrich E KruseRobert N WeinrebLouis R PasqualeJonathan L HainesUnnur ThorsteinsdottirFridbert JonassonR Rand AllinghamDan MileaRobert RitchToshiaki KubotaKei TashiroEranga N VithanaShazia MichealFotis TopouzisJamie E CraigMichael V DubinaPeriasamy SundaresanKari StefanssonJaney L WiggsFrancesca PasuttoChiea Chuen KhorPublished in: Nature genetics (2017)
Exfoliation syndrome (XFS) is the most common known risk factor for secondary glaucoma and a major cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A, have previously been associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results across populations, and to identify new variants associated with XFS. We identified a rare protective allele at LOXL1 (p.Phe407, odds ratio (OR) = 25, P = 2.9 × 10-14) through deep resequencing of XFS cases and controls from nine countries. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 × 10-8). We identified association signals at 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.