biostudies-literatureIglesias AINEI NIH HHSBritish Heart FoundationNCATS NIH HHSMedical Research CouncilNational Institute for Health Research (NIHR)NIH HHS1864https://www.ebi.ac.uk/biostudies/studies/S-EPMC5951816biostudies-literatureUnknown9(1)Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r = -0.62, P Nature communicationsCross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases.PMC5951816HDR-1004R01 EY023242MC_UU_00007/10UL1 TR001881R01 EY022305HDR-9004G19/2NF-SI-0617-10113S10 OD018164MR/L003120/1RG/13/13/30194NF-SI-0512-10165P30 EY014104MC_PC_U127561128R01 EY009052Yazar SRicketts MMartin NGZhang KVukcevic DUitterlinden AGGaasterland DDuncanson ASawcer SJMoroi SEPlomin RWood NWShi YPericak-Vance MASchuman JSMathew CGWilloughby CEGaasterland TBand GBonnemaijer PKhawaja APHauser MASu ZWidaa SBrilliant MHHayward CHolliday EGTrembath RCBlackwell JMPotter SCVollrath DCorvin ALoomis SJWollstein GStaffieri SEViswanathan ABailey JNCPasquale LRZeller TPfeiffer NRealini AWeinreb RNSouzeau EAllingham RRWhittaker PChristen WGZack DJDeloukas PSit AJDonnelly PPirinen MBykhovskaya YKhor CCWang JJLiddle JTaylor KDBrown MAHewitt AWMitchell PCuellar-Partida GNag AGiannoulatou EHunt SEGray EMishra AHohn RPearson RKang JHKlaver CCWMackey DARochtchina EPalmer CNARotter JILee RKBurdon KPLucas SEMWilson JFAung TRautanen AInouye MLichter PRHammond NRichards JESingh KGharahkhani PXie JHammond CJBellenguez CKearns LSMcCann OTRabinowitz YSMills RABarroso IGwilliam RSpringelkamp HEdkins SMarkus HSFreeman CCasas JPSpencer CCAWaller MBramon Evan Duijn CMCheng CYLi XWong TYWeston PVithana ENBudenz DLvan Leeuwen EMMacGregor SGillman MIglesias AIAttia JNEIGHBORHOOD ConsortiumKraft PPolasek OBlackburn HBumpstead SJBeutel MEHaines JLRavindrarajah RHysi PGLiu YLangford CSiscovick DScott RScott WKJankowski JSchmidtmann IMontgomery GWHellenthal GDronov STham YCVitart VBaird PNSim XWellcome Trust Case Control Consortium 2 (WTCCC2)Friedman DSFingert JBlue Mountains Eye Study—GWAS groupJonas JBWiggs JLFoster PJBoutin TCraig JEStrange AJayakumar AfalseCross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases.Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r = -0.62, P 2018-01-01T00:00:00Z2018 May2026-04-13T07:15:50.277Z2019-03-26T22:35:29ZS-EPMC59518162976044210.1038/s41467-018-03646-6