Cross-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 = 5.30 × 10-5) but not between CCT and primary open-angle glaucoma (r = -0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation.
Iglesias, AI; Mishra, A; Vitart, V; Bykhovskaya, Y; Höhn, R; Springelkamp, H; Cuellar-Partida, G; Gharahkhani, P; Bailey, JNC; Willoughby, CE; Li, X; Yazar, S; Nag, A; Khawaja, AP; Polašek, O; Siscovick, D; Mitchell, P; Tham, YC; Haines, JL; Kearns, LS; Hayward, C; Shi, Y; van Leeuwen, EM; Taylor, KD; Blue Mountains Eye Study—GWAS group, ; Bonnemaijer, P; Rotter, JI; Martin, NG; Zeller, T; Mills, RA; Souzeau, E; Staffieri, SE; Jonas, JB; Schmidtmann, I; Boutin, T; Kang, JH; Lucas, SEM; Wong, TY; Beutel, ME; Wilson, JF; NEIGHBORHOOD Consortium, ; Wellcome Trust Case Control Consortium 2 (WTCCC2), ; Uitterlinden, AG; Vithana, EN; Foster, PJ; Hysi, PG; Hewitt, AW; Khor, CC; Pasquale, LR; Montgomery, GW; Klaver, CCW; Aung, T; Pfeiffer, N; Mackey, DA; Hammond, CJ; Cheng, C-Y; Craig, JE; Rabinowitz, YS; Wiggs, JL; Burdon, KP; van Duijn, CM; MacGregor, S
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