Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases.
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 None., Bonnemaijer P., Rotter JI., Martin NG., Zeller T., Mills RA., Souzeau E., Staffieri SE., Jonas JB., Schmidtmann I., Boutin T., Kang JH., Kang JH., Lucas SEM., Wong TY., Beutel ME., Wilson JF., NEIGHBORHOOD Consortium None., Wellcome Trust Case Control Consortium 2 (WTCCC2) None., 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.
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.