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


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Iglesias, AI, Mishra, A, Vitart, V, Bykhovskaya, Y, Hohn, R, Springelkamp, H, Cuellar-Partida, G, Gharahkhani, P, Cooke Bailey, JN, Willoughby, CE, Li, Xiaohui, Yazar, S, Nag, A, Khawaja, AP, Polasek, O, Siscovick, D, Mitchell, P, Tham, YC, Haines, JL, Kearns, LS, Hayward, C, Shi, Y, van Leeuwen, EM, Taylor, KD, Bonnemaijer, P, Rotter, JI, Martin, NG, Zeller, T, Mills, RA, Staffieri, SE, Jonas, JB, Schmidtmann, I, Boutin, T, Kang, JH, Lucas, SEM ORCID: 0000-0003-0104-5406, Wong, TY, Beutel, ME, Wilson, JF, Uitterlinden, AG, Vithana, EN, Foster, PJ, Hysi, PG, Hewitt, AW ORCID: 0000-0002-5123-5999, Khor, CC, Pasquale, LR, Montgomery, GW, Klaver, CCW, Aung, T, Pfeiffer, N, Mackey, DA, Hammond, CJ, Cheng, CY, Craig, JE, Rabinowitz, YS, Wiggs, JL, Burdon, KP ORCID: 0000-0001-8217-1249, van Duijn, CM and MacGregor, S 2018 , 'Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases' , Nature Communications, vol. 9, no. 1 , pp. 1-11 , doi: 10.1038/s41467-018-03646-6.

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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.

Item Type: Article
Authors/Creators:Iglesias, AI and Mishra, A and Vitart, V and Bykhovskaya, Y and Hohn, R and Springelkamp, H and Cuellar-Partida, G and Gharahkhani, P and Cooke Bailey, JN and Willoughby, CE and Li, Xiaohui and Yazar, S and Nag, A and Khawaja, AP and Polasek, O and Siscovick, D and Mitchell, P and Tham, YC and Haines, JL and Kearns, LS and Hayward, C and Shi, Y and van Leeuwen, EM and Taylor, KD and Bonnemaijer, P and Rotter, JI and Martin, NG and Zeller, T and Mills, RA and Staffieri, SE and Jonas, JB and Schmidtmann, I and Boutin, T and Kang, JH and Lucas, SEM and Wong, TY and Beutel, ME and Wilson, JF and Uitterlinden, AG and Vithana, EN and Foster, PJ and Hysi, PG and Hewitt, AW and Khor, CC and Pasquale, LR and Montgomery, GW and Klaver, CCW and Aung, T and Pfeiffer, N and Mackey, DA and Hammond, CJ and Cheng, CY and Craig, JE and Rabinowitz, YS and Wiggs, JL and Burdon, KP and van Duijn, CM and MacGregor, S
Keywords: cornea, keratoconus, glaucoma, association
Journal or Publication Title: Nature Communications
Publisher: Nature Publishing Group
ISSN: 2041-1723
DOI / ID Number: 10.1038/s41467-018-03646-6
Copyright Information:

© 2018 The Authors. Licensed under Creative Commons Attribution 4.0 International (CC BY 4.0)

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