Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases Academic Article uri icon

abstract

  • 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.

authors

  • 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
  • Wang, JJ
  • Rochtchina, E
  • Attia, J
  • Scott, R
  • Holliday, EG
  • Baird, PN
  • Xie, J
  • Inouye, Michael
  • Viswanathan, A
  • Sim, X
  • Bonnemaijer, P
  • Rotter, JI
  • Martin, NG
  • Zeller, T
  • Mills, RA
  • Staffieri, SE
  • Jonas, JB
  • Schmidtmann, I
  • Boutin, T
  • Kang, JH
  • Lucas, SEM
  • Wong, TY
  • Beutel, ME
  • Wilson, JF
  • Allingham, RR
  • Brilliant, MH
  • Budenz, DL
  • Christen, WG
  • Fingert, J
  • Friedman, DS
  • Gaasterland, D
  • Gaasterland, T
  • Hauser, MA
  • Kraft, P
  • Lee, RK
  • Lichter, PR
  • Liu, Y
  • Loomis, SJ
  • Moroi, SE
  • Pericak-Vance, MA
  • Realini, A
  • Richards, JE
  • Schuman, JS
  • Scott, WK
  • Singh, K
  • Sit, AJ
  • Vollrath, D
  • Weinreb, RN
  • Wollstein, G
  • Zack, DJ
  • Zhang, K
  • Donnelly, P
  • Barroso, I
  • Blackwell, JM
  • Bramon, E
  • Brown, MA
  • Casas, JP
  • Corvin, A
  • Deloukas, P
  • Duncanson, A
  • Jankowski, J
  • Markus, HS
  • Mathew, CG
  • Palmer, CNA
  • Plomin, R
  • Rautanen, A
  • Sawcer, SJ
  • Trembath, RC
  • Wood, NW
  • Spencer, CCA
  • Band, G
  • Bellenguez, C
  • Freeman, C
  • Hellenthal, G
  • Giannoulatou, E
  • Pirinen, M

publication date

  • 2018

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