Genome-wide association study identifies WNT7B as a novel locus for central corneal thickness in Latinos.

The cornea is the outermost layer of the eye and is a vital component of focusing incoming light on the retina. Central corneal thickness (CCT) is now recognized to have a significant role in ocular health and is a risk factor for various ocular diseases, such as keratoconus and primary open angle glaucoma. Most previous genetic studies utilized European and Asian subjects to identify genetic loci associated with CCT. Minority populations, such as Latinos, may aid in identifying additional loci and improve our understanding of the genetic architecture of CCT. In this study, we conducted a genome-wide association study (GWAS) in Latinos, a traditionally understudied population in genetic research, to further identify loci contributing to CCT. Study participants were genotyped using either the Illumina OmniExpress BeadChip (∼730K markers) or the Illumina Hispanic/SOL BeadChip (∼2.5 million markers). All study participants were 40 years of age and older. We assessed the association between individual single nucleotide polymorphisms (SNPs) and CCT using linear regression, adjusting for age, gender and principal components of genetic ancestry. To expand genomic coverage and to interrogate additional SNPs, we imputed SNPs from the 1000 Genomes Project reference panels. We identified a novel SNP, rs10453441 (P = 6.01E-09), in an intron of WNT7B that is associated with CCT. Furthermore, WNT7B is expressed in the human cornea. We also replicated 11 previously reported loci, including IBTK, RXRA-COL5A1, COL5A1, FOXO1, LRRK1 and ZNF469 (P < 1.25E-3). These findings provide further insight into the genetic architecture of CCT and illustrate that the use of minority groups in GWAS will help identify additional loci.

[1]  Michael Boehnke,et al.  Quantifying and correcting for the winner's curse in quantitative‐trait association studies , 2011, Genetic epidemiology.

[2]  Paul Marjoram,et al.  Genotype Imputation for Latinos Using the HapMap and 1000 Genomes Project Reference Panels , 2012, Front. Gene..

[3]  R. Mei,et al.  A genomewide admixture mapping panel for Hispanic/Latino populations. , 2007, American journal of human genetics.

[4]  D. Reich,et al.  Population Structure and Eigenanalysis , 2006, PLoS genetics.

[5]  P. Brown,et al.  Differential gene expression in anatomical compartments of the human eye , 2005, Genome Biology.

[6]  Shan C. Lin,et al.  Central corneal thickness of Caucasians, Chinese, Hispanics, Filipinos, African Americans, and Japanese in a glaucoma clinic. , 2004, Ophthalmology.

[7]  J. Haines,et al.  Family-based Genome-wide Association Study in South Indian Consanguineous Pedigrees Identifies an Association between WNT7B and Central Corneal Thickness , 2013 .

[8]  S. Azen,et al.  Baseline risk factors that predict the development of open-angle glaucoma in a population: the Los Angeles Latino Eye Study. , 2012, Ophthalmology.

[9]  Xiaoyi Gao.  Multiple testing corrections for imputed SNPs , 2011, Genetic epidemiology.

[10]  N. Fullwood,et al.  Tight junction-related protein expression and distribution in human corneal epithelium. , 2003, Experimental eye research.

[11]  J. Craig,et al.  The genetics of central corneal thickness , 2009, British Journal of Ophthalmology.

[12]  Michael Boehnke,et al.  Quantifying and correcting for the winner's curse in genetic association studies , 2009, Genetic epidemiology.

[13]  M. Province,et al.  Avoiding the high Bonferroni penalty in genome‐wide association studies , 2009, Genetic epidemiology.

[14]  Tin Aung,et al.  Collagen-related genes influence the glaucoma risk factor, central corneal thickness. , 2011, Human molecular genetics.

[15]  M. C. Leske,et al.  Risk factors for incident open-angle glaucoma: the Barbados Eye Studies. , 2008, Ophthalmology.

[16]  M. Rieder,et al.  Optimal unified approach for rare-variant association testing with application to small-sample case-control whole-exome sequencing studies. , 2012, American journal of human genetics.

[17]  F. X. Yu,et al.  Role of ErbB2 in Corneal Epithelial Wound Healing. , 2004, Investigative ophthalmology & visual science.

[18]  W. Gauderman.  Sample size requirements for association studies of gene-gene interaction. , 2002, American journal of epidemiology.

[19]  Olivier Delaneau,et al.  Integrating sequence and array data to create an improved 1000 Genomes Project haplotype reference panel , 2014, Nature Communications.

[20]  A. Hofman,et al.  Distribution of central corneal thickness and its association with intraocular pressure: The Rotterdam Study. , 1997, American journal of ophthalmology.

[21]  Paul Marjoram,et al.  A genome-wide association study of central corneal thickness in Latinos. , 2013, Investigative ophthalmology & visual science.

[22]  A. Lambiase,et al.  Nerve growth factor promotes corneal healing: structural, biochemical, and molecular analyses of rat and human corneas. , 2000, Investigative ophthalmology & visual science.

[23]  M. C. Leske,et al.  Corneal thickness and intraocular pressure in the Barbados eye studies. , 2003, Archives of ophthalmology.

[24]  Michael Boehnke,et al.  LocusZoom: regional visualization of genome-wide association scan results , 2010, Bioinform..

[25]  P. Mitchell,et al.  Novel quantitative trait loci for central corneal thickness identified by candidate gene analysis of osteogenesis imperfecta genes , 2009, Human Genetics.

[26]  Paul Mitchell,et al.  Common Genetic Variants near the Brittle Cornea Syndrome Locus ZNF469 Influence the Blinding Disease Risk Factor Central Corneal Thickness , 2010, PLoS genetics.

[27]  A. Sekine,et al.  Edinburgh Research Explorer Identification of myopia-associated WNT7B polymorphisms provides insights into the mechanism underlying the development of myopia , 2022 .

[28]  S. Azen,et al.  Prevalence of open-angle glaucoma and ocular hypertension in Latinos: the Los Angeles Latino Eye Study. , 2003, Ophthalmology.

[29]  F. Yu,et al.  Wnt/β-catenin signaling regulates proliferation of human cornea epithelial stem/progenitor cells. , 2011, Investigative ophthalmology & visual science.

[30]  Tin Aung,et al.  Genome-wide association analyses identify multiple loci associated with central corneal thickness and keratoconus , 2013, Nature Genetics.

[31]  James S Wolffsohn,et al.  Keratoconus: a review. , 2010, Contact lens & anterior eye : the journal of the British Contact Lens Association.

[32]  Chris A. Johnson,et al.  The Ocular Hypertension Treatment Study: baseline factors that predict the onset of primary open-angle glaucoma. , 2002, Archives of ophthalmology.

[33]  Mei-Ju Chen,et al.  Relationship Between Central Corneal Thickness, Refractive Error, Corneal Curvature, Anterior Chamber Depth and Axial Length , 2009, Journal of the Chinese Medical Association : JCMA.

[34]  Jost B Jonas,et al.  Identification of four novel variants that influence central corneal thickness in multi-ethnic Asian populations. , 2012, Human molecular genetics.

[35]  C. Joo,et al.  Wnt-7a Up-regulates Matrix Metalloproteinase-12 Expression and Promotes Cell Proliferation in Corneal Epithelial Cells during Wound Healing* , 2005, Journal of Biological Chemistry.

[36]  S. Miglior,et al.  Predictive factors for open-angle glaucoma among patients with ocular hypertension in the European Glaucoma Prevention Study. , 2007, Ophthalmology.

[37]  Carson C Chow,et al.  Second-generation PLINK: rising to the challenge of larger and richer datasets , 2014, GigaScience.

[38]  Jing Wang,et al.  WEB-based GEne SeT AnaLysis Toolkit (WebGestalt): update 2013 , 2013, Nucleic Acids Res..

[39]  Yun Li,et al.  METAL: fast and efficient meta-analysis of genomewide association scans , 2010, Bioinform..

[40]  J. Clayton-Smith,et al.  Brittle cornea syndrome: recognition, molecular diagnosis and management , 2013, Orphanet Journal of Rare Diseases.

[41]  Igor Rudan,et al.  New loci associated with central cornea thickness include COL5A1, AKAP13 and AVGR8. , 2010, Human molecular genetics.

[42]  Kenny Q. Ye,et al.  An integrated map of genetic variation from 1,092 human genomes , 2012, Nature.

[43]  D. Wakefield,et al.  The phenotype of limbal epithelial stem cells. , 2007, Investigative ophthalmology & visual science.

[44]  Tanja Zeller,et al.  Population-based meta-analysis in Caucasians confirms association with COL5A1 and ZNF469 but not COL8A2 with central corneal thickness , 2012, Human Genetics.

[45]  M. Senchyna,et al.  Presence and distribution of 14-3-3 proteins in human ocular surface tissues , 2008, Molecular vision.

[46]  Eden R Martin,et al.  A multiple testing correction method for genetic association studies using correlated single nucleotide polymorphisms , 2008, Genetic epidemiology.

[47]  J. L. Poulsen,et al.  Central corneal thickness is highly heritable: the twin eye studies. , 2005, Investigative ophthalmology & visual science.

[48]  S. Azen,et al.  Central corneal thickness in Latinos. , 2003, Investigative ophthalmology & visual science.

[49]  Shelley B. Bull,et al.  BR-squared: a practical solution to the winner’s curse in genome-wide scans , 2011, Human Genetics.

[50]  Gadi Wollstein,et al.  Genome-wide analysis of central corneal thickness in primary open-angle glaucoma cases in the NEIGHBOR and GLAUGEN consortia. , 2012, Investigative ophthalmology & visual science.

[51]  Y. Kariya,et al.  Insulin-like growth factor-1 induces migration and expression of laminin-5 in cultured human corneal epithelial cells. , 2006, Investigative ophthalmology & visual science.

[52]  M. C. Leske,et al.  Predictors of long-term progression in the early manifest glaucoma trial. , 2007, Ophthalmology.

[53]  Donald J. Brown,et al.  Expression of neuregulin 1, a member of the epidermal growth factor family, is expressed as multiple splice variants in the adult human cornea. , 2004, Investigative ophthalmology & visual science.

[54]  K. Roeder,et al.  Genomic Control for Association Studies , 1999, Biometrics.

[55]  P. Alsbirk,et al.  CORNEAL THICKNESS: II. Environmental and Genetic Factors , 1978, Acta ophthalmologica.

[56]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[57]  W James Gauderman,et al.  Sample size requirements for matched case‐control studies of gene–environment interaction , 2002, Statistics in medicine.