A genome-wide association study of central corneal thickness in Latinos.

PURPOSE Central corneal thickness (CCT) is a clinically important risk factor for primary open-angle glaucoma and keratoconus. Genetic factors controlling CCT in Latinos, the most populous minority population in the United States, are unclear. Here we describe the first genome-wide association study (GWAS) report of CCT in Latinos. METHODS We performed a GWAS for CCT on 1768 Latinos recruited in the Los Angeles Latino Eye Study (LALES) using Illumina's HumanOmniExpress BeadChip (∼730K markers). To discover additional associated single-nucleotide polymorphisms (SNPs), we imputed SNPs based on the 1000 Genomes Project reference panels. All subjects were 40 years of age and older. We used linear regression with adjustment for age, sex, and principal components of genetic ancestry. RESULTS we replicated the involvement of several previously reported loci, SUCH AS RXRA-COL5A1, FOXO1, and ZNF469, for CCT in Latinos (P 0.002). moreover, we discovered novel SNPS, RS3118515, RS943423, RS3118594, AND RS3132307, THAT REACHED GWAS SIGNIFICANCE (P 5 10(8)) in the uncharacterized LOC100506532 (GENE TYPE: miscRNA) for CCT in Latinos. By conditional analysis, we demonstrate that rs3118515 in this gene is responsible for the GWAS signal in the chromosome 9 RXRA-COL5A1 region in Latinos. Moreover, multiple sources of ENCODE evidence suggest that rs3118515 is in a regulatory region. Reverse-transcription PCR products indicated that transcripts of LOC100506532 surrounding rs3118515 were expressed in human corneas. CONCLUSIONS We discovered novel SNPs for CCT in Latinos and provided the first reported evidence of the corneal expression of LOC100506532. These results help to further increase our understanding of the genetic architecture of CCT.

[1]  R Core Team,et al.  R: A language and environment for statistical computing. , 2014 .

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

[3]  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.

[4]  Data production leads,et al.  An integrated encyclopedia of DNA elements in the human genome , 2012 .

[5]  Raymond K. Auerbach,et al.  An Integrated Encyclopedia of DNA Elements in the Human Genome , 2012, Nature.

[6]  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.

[7]  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.

[8]  B. Faircloth,et al.  Primer3—new capabilities and interfaces , 2012, Nucleic acids research.

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

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

[11]  Martin Renqiang Min,et al.  An integrated encyclopedia of DNA elements in the human genome , 2012 .

[12]  S. Azen,et al.  Population and high-risk group screening for glaucoma: the Los Angeles Latino Eye Study. , 2011, Investigative ophthalmology & visual science.

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

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

[15]  Talin Haritunians,et al.  Variants in ZNF365 isoform D are associated with Crohn's disease , 2011, Gut.

[16]  M. Teus,et al.  Central corneal thickness in a healthy Spanish population , 2011 .

[17]  G. Abecasis,et al.  MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes , 2010, Genetic epidemiology.

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

[19]  Sharon R Grossman,et al.  Integrating common and rare genetic variation in diverse human populations , 2010, Nature.

[20]  J. Wiggs,et al.  Glaucoma: genes, phenotypes, and new directions for therapy. , 2010, The Journal of clinical investigation.

[21]  Olle Melander,et al.  From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus , 2010, Nature.

[22]  Tanya M. Teslovich,et al.  Biological, Clinical, and Population Relevance of 95 Loci for Blood Lipids , 2010, Nature.

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

[24]  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.

[25]  D. Mackey,et al.  Heritability of central corneal thickness in nuclear families. , 2009, Investigative ophthalmology & visual science.

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

[27]  Liang Xu,et al.  The Beijing Eye Study , 2009, Acta ophthalmologica.

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

[29]  G. Cioffi,et al.  Central corneal thickness in Northwestern American Indians/Alaskan Natives and comparison with White and African-American persons. , 2008, American journal of ophthalmology.

[30]  Jian Zhang,et al.  Heritability of central corneal thickness in Chinese: the Guangzhou Twin Eye Study. , 2008, Investigative ophthalmology & visual science.

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

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

[33]  Liu Pengcheng,et al.  Central corneal thickness in adult Chinese , 2008, Journal of Huazhong University of Science and Technology [Medical Sciences].

[34]  J. Jonas,et al.  Central corneal thickness in adult Chinese. Association with ocular and general parameters. The Beijing Eye Study , 2008, Graefe's Archive for Clinical and Experimental Ophthalmology.

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

[36]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

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

[38]  A. Fazelzadeh,et al.  Central corneal thickness as a risk factor for glaucoma. , 2007, Medical hypotheses.

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

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

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

[42]  A. Iwase,et al.  Corneal thickness in an ophthalmologically normal Japanese population. , 2005, Ophthalmology.

[43]  R. Klein,et al.  The Los Angeles Latino Eye Study: design, methods, and baseline data. , 2004, Ophthalmology.

[44]  L. Herndon,et al.  Central corneal thickness as a risk factor for advanced glaucoma damage. , 2003, Archives of ophthalmology.

[45]  W. Gauderman.  Candidate gene association analysis for a quantitative trait, using parent‐offspring trios , 2003, Genetic epidemiology.

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

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

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

[49]  Kazuyuki Sasaki,et al.  Central corneal thickness, radius of the corneal curvature and intraocular pressure in normal subjects using non-contact techniques: Reykjavik Eye Study. , 2002, Acta ophthalmologica Scandinavica.

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

[51]  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.

[52]  Gerhard K. Lang,et al.  Ophthalmology: A Pocket Textbook Atlas , 2000 .

[53]  S Rozen,et al.  Primer3 on the WWW for general users and for biologist programmers. , 2000, Methods in molecular biology.

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

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

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