Genome-wide association analyses identify multiple loci associated with central corneal thickness and keratoconus

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Central corneal thickness (CCT) is associated with eye conditions including keratoconus and glaucoma. We performed a meta-analysis on >20,000 individuals in European and Asian populations that identified 16 new loci associated with CCT at genome-wide significance (P < 5 × 10−8). We further showed that 2 CCT-associated loci, FOXO1 and FNDC3B, conferred relatively large risks for keratoconus in 2 cohorts with 874 cases and 6,085 controls (rs2721051 near FOXO1 had odds ratio (OR) = 1.62, 95% confidence interval (CI) = 1.4–1.88, P = 2.7 × 10−10, and rs4894535 in FNDC3B had OR = 1.47, 95% CI = 1.29–1.68, P = 4.9 × 10−9). FNDC3B was also associated with primary open-angle glaucoma (P = 5.6 × 10−4; tested in 3 cohorts with 2,979 cases and 7,399 controls). Further analyses implicate the collagen and extracellular matrix pathways in the regulation of CCT.

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Figure 1: Manhattan plot of set 1 meta-analysis results.
Figure 2: Association with CCT in European and Asian populations, and with keratoconus risk in European populations.


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A list of acknowledgments by study is provided in the Supplementary Note.

Author information

S.M., V.V., D.A.M., T.Y.W. and Y.L. conceived and designed the study, and liaised with the International Glaucoma Genetics Consortium for this project. Y.L. performed the primary analyses. S.M., J.Y., M.U., X.L., C.C.K., E.N.V., T.A., K.P.B., G.T., F.J., V.V., O.P., D.Y.L.L., L.J.C., C.C.Y.T., R.C., D.K., W.A., W.D.R., V.J.M.V., H.S., J.G., A.J.C., A. MacLeod, S.E., P.G.H., Y.B. and X.L. contributed to analysis. S.M. and Y.L. performed pathway analysis. J.E.C., P.M., U.T., A.F.W., N.P., C.P.P., M.G.A., J.L.W., M.A.H., L.R.P., C.E.W., N.G.M., D.A.M., C.M.v.D., T.Y.W., A.J.L., C.J.H. and Y.S.R. were the overseeing principal investigators of the individual studies. J.E.C., K.P.B., D.P.D., R.A.M., G.T., K.S., F.J., U.T., A.F.W., V.V., I.R., Z.V., C.H., O.P., H.C., J.F.W., B.F., N.P., A. Mirshahi, T.Z., R.H., F.G., R.C., K.J.L., C.P.P., D.Y.L.L., L.J.C., C.C.Y.T., M.G.A., D.K., J.L.W., L.R.P., M.U., J. Liu, B.L.Y., A.B.O., J.E.R., S.E.M., J.L.H., J.H.K., L.R.P., R.R.A., A.A.-K., J.L.W., M.A.H., N.G.M., Y.L., G.W.M., S.M., D.A.M., A.W.H., J.M., W.A., S.Y., C.P., T.L.Y., W.D.R., V.J.M.V., R.W., H.S., C.C.W.K., C.M.v.D., C.C.K., E.N.V., B.K.C., W.-T.T., E.S.T., C.-Y.C., J.-N.F., J. Li, S.M.S., T.A., T.Y.W., J.G., A.J.C., A. MacLeod, S.E., A.J.L., P.G.H., T.D.S., T.L.Y. and C.J.H. contributed reagents or methods to the genotyping, phenotyping and data analysis of corneal thickness data sets. J.E.C., K.P.B., D.P.D., R.A.M., C.P.P., D.Y.L.L., L.J.C., C.C.Y.T., J.L.W., L.R.P., M.U., J. Li, B.L.Y., A.B.O., J.E.R., S.E.M., J.L.H., J.H.K., L.R.P., R.R.A., A.A.-K., J.L.W., M.A.H., C.E.W., A.J.L., J.G., A.J.C., A. MacLeod, S.E., Y.S.R., Y.B., X.L., D.S., K.D.T., J.J.W., A.C.V. and J.I.R. contributed reagents or the genotyping, phenotyping and data analysis of the glaucoma, and keratoconus samples. Y.L. and S.M. wrote the first draft of this manuscript. K.P.B., V.V., C.C.K., Y.B., A. Mirshahi, A.W.H., D.K., P.G.H., W.D.R., J.L.W., C.M.v.D., Y.S.R., D.A.M., J.E.C. and T.Y.W. provided critical comments for manuscript revision. All authors reviewed the final manuscript.

Correspondence to Stuart Macgregor or Tien Y Wong.

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A list of members is provided in the Supplementary Note.

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Lu, Y., Vitart, V., Burdon, K. et al. Genome-wide association analyses identify multiple loci associated with central corneal thickness and keratoconus. Nat Genet 45, 155–163 (2013) doi:10.1038/ng.2506

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