Family-based genome-wide association study of south Indian pedigrees supports WNT7B as a central corneal thickness locus

Bao Jian Fan, Xueli Chen, Nisha Sondhi, P. Ferdinamarie Sharmila, Nagasamy Soumittra, Sarangapani Sripriya, Srinivasan Sacikala, Rashima Asokan, David S. Friedman, Louis R. Pasquale, X. Raymond Gao, Lingam Vijaya, Jessica Cooke Bailey, Veronique Vitart, Stuart Macgregor, Christopher J. Hammond, Chiea Chuen Khor, Jonathan L. Haines, Ronnie George, Janey L. WiggsR. Rand Allingham, Jim Gauderman, Michael Hauser, Jerome I. Rotter, Rohit Varma, Tin Aung, Kathryn P. Burdon, Ching Yu Cheng, Jamie E. Craig, Angela J. Cree, Puya Gharahkhani, Alex W. Hewitt, René Höhn, Pirro Hysi, Adriana I. Iglesias Gonzalez, Jost Jonas, Anthony Khawaja, Caroline C.W. Klaver, Francesca Pasutto, David Mackey, Paul Mitchell, Aniket Mishra, Calvin Pang, Henriette Springelkamp, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Cornelia M. van Duijn, Ananth Viswanathan, Robert Wojciechowski, Tien Wong, Terri L. Young, Tanja Zeller, Murray Brilliant, Don Budenz, John Fingert, Douglas Gaasterland, Teresa Gaasterland, Rob Igo, Jae Hee Kang, Peter Kraft, Richard Lee, Paul Lichter, Yutao Liu, Syoko Moroi, Anthony Realini, Doug Rhee, Julia R. Richards, Robert Ritch, Joel Schuman, William K. Scott, Kuldev Singh, Arthur Sit, Douglas Vollrath, Robert N. Weinreb, Gadi Wollstein, Don Zack

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Abstract

Purpose: To identify genetic risk factors contributing to central corneal thickness (CCT) in individuals from South India, a population with a high prevalence of ocular disorders. Methods: One hundred ninety-five individuals from 15 large South Indian pedigrees were genotyped using the Omni2.5 bead array. Family-based association for CCT was conducted using the score test in MERLIN. Results: Genome-wide association study (GWAS) identified strongest association for single nucleotide polymorphisms (SNPs) in the first intron of WNT7B and CCT (top SNP rs9330813; β = −0.57, 95% confidence interval CI: −0.78 to −0.36; P = 1.7 × 10−7). We further investigated rs9330813 in a Latino cohort and four independent European cohorts. A meta-analysis of these data sets demonstrated statistically significant association between rs9330813 and CCT (β = −3.94, 95% CI: −5.23 to −2.66; P = 1.7 × 10−9). WNT7B SNPs located in the same genomic region that includes rs9330813 have previously been associated with CCT in Latinos but with other ocular quantitative traits related to myopia (corneal curvature and axial length) in a Japanese population (rs10453441 and rs200329677). To evaluate the specificity of the observed WNT7B association with CCT in the South Indian families, we completed an ocular phenome-wide association study (PheWAS) for the top WNT7B SNPs using 45 ocular traits measured in these same families including corneal curvature and axial length. The ocular PheWAS results indicate that in the South Indian families WNT7B SNPs are primarily associated with CCT. Conclusions: The results indicate robust evidence for association between WNT7B SNPs and CCT in South Indian pedigrees, and suggest that WNT7B SNPs can have population-specific effects on ocular quantitative traits.

Original languageEnglish (US)
Pages (from-to)2495-2502
Number of pages8
JournalInvestigative Ophthalmology and Visual Science
Volume59
Issue number6
DOIs
StatePublished - May 1 2018

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Keywords

  • Cornea central thickness
  • Genetic association
  • Ocular PheWAS
  • Quantitative trait
  • WNT7B

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Fan, B. J., Chen, X., Sondhi, N., Sharmila, P. F., Soumittra, N., Sripriya, S., Sacikala, S., Asokan, R., Friedman, D. S., Pasquale, L. R., Gao, X. R., Vijaya, L., Bailey, J. C., Vitart, V., Macgregor, S., Hammond, C. J., Khor, C. C., Haines, J. L., George, R., ... Zack, D. (2018). Family-based genome-wide association study of south Indian pedigrees supports WNT7B as a central corneal thickness locus. Investigative Ophthalmology and Visual Science, 59(6), 2495-2502. https://doi.org/10.1167/iovs.17-23536