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Genome-wide association meta-analysis of corneal curvature identifies novel loci and shared genetic influences across axial length and refractive error.

ABSTRACT: Corneal curvature, a highly heritable trait, is a key clinical endophenotype for myopia - a major cause of visual impairment and blindness in the world. Here we present a trans-ethnic meta-analysis of corneal curvature GWAS in 44,042 individuals of Caucasian and Asian with replication in 88,218 UK Biobank data. We identified 47 loci (of which 26 are novel), with population-specific signals as well as shared signals across ethnicities. Some identified variants showed precise scaling in corneal curvature and eye elongation (i.e. axial length) to maintain eyes in emmetropia (i.e. HDAC11/FBLN2 rs2630445, RBP3 rs11204213); others exhibited association with myopia with little pleiotropic effects on eye elongation. Implicated genes are involved in extracellular matrix organization, developmental process for body and eye, connective tissue cartilage and glycosylation protein activities. Our study provides insights into population-specific novel genes for corneal curvature, and their pleiotropic effect in regulating eye size or conferring susceptibility to myopia.

SUBMITTER: Fan Q

PROVIDER: S-EPMC7081241 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Genome-wide association meta-analysis of corneal curvature identifies novel loci and shared genetic influences across axial length and refractive error.

Fan Qiao Q Pozarickij Alfred A Tan Nicholas Y Q NYQ Guo Xiaobo X Verhoeven Virginie J M VJM Vitart Veronique V Guggenheim Jeremy A JA Miyake Masahiro M Tideman J Willem L JWL Khawaja Anthony P AP Zhang Liang L MacGregor Stuart S Höhn René R Chen Peng P Biino Ginevra G Wedenoja Juho J Saffari Seyed Ehsan SE Tedja Milly S MS Xie Jing J Lanca Carla C Wang Ya Xing YX Sahebjada Srujana S Mazur Johanna J Mirshahi Alireza A Martin Nicholas G NG Yazar Seyhan S Pennell Craig E CE Yap Maurice M Haarman Annechien E G AEG Enthoven Clair A CA Polling JanRoelof J Hewitt Alex W AW Jaddoe Vincent W V VWV van Duijn Cornelia M CM Hayward Caroline C Polasek Ozren O Tai E-Shyong ES Yoshikatsu Hosoda H Hysi Pirro G PG Young Terri L TL Tsujikawa Akitaka A Wang Jie Jing JJ Mitchell Paul P Pfeiffer Norbert N Pärssinen Olavi O Foster Paul J PJ Fossarello Maurizio M Yip Shea Ping SP Williams Cathy C Hammond Christopher J CJ Jonas Jost B JB He Mingguang M Mackey David A DA Wong Tien-Yin TY Klaver Caroline C W CCW Saw Seang-Mei SM Baird Paul N PN Cheng Ching-Yu CY

Communications biology 20200319 1

Corneal curvature, a highly heritable trait, is a key clinical endophenotype for myopia - a major cause of visual impairment and blindness in the world. Here we present a trans-ethnic meta-analysis of corneal curvature GWAS in 44,042 individuals of Caucasian and Asian with replication in 88,218 UK Biobank data. We identified 47 loci (of which 26 are novel), with population-specific signals as well as shared signals across ethnicities. Some identified variants showed precise scaling in corneal cu ...[more]

PMID: 32193507

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Project description:BackgroundMyopia is a common eye disorder that is approaching epidemic proportions worldwide. A genome-wide association study identified AREG (rs12511037), GABRR1 (rs13215566), and PDE10A (rs12206610) as being associated with refractive error in Asian populations. The present study investigated the associations between these three genetic variants and the occurrence and development of myopia, spherical equivalent refraction (SER), axial length (AL), and corneal curvature (CC) in a cohort of southeastern Chinese schoolchildren.MethodsWe examined and followed 550 children in grade 1 enrolled in the Wenzhou Epidemiology of Refractive Error (WERE) project. During the 4-year follow-up, non-cycloplegic refraction was evaluated twice each year, and the AL and CC were measured once every year. Age, sex, and the amounts of time spent on near work and outdoors were documented with a questionnaire. Sanger DNA sequencing was used to genotype single nucleotide polymorphisms (SNPs). SNPtest software was used to identify potential genetic variants associated with myopia, SER, AL, and CC. Ten thousand permutations were used to correct for multiple testing.ResultsIn total, 469 children, including 249 (53.1%) boys and 220 (46.9%) girls, were included in analyses. The mean age of all the children was 6.33 ± 0.48 years. After adjusting for age, sex, time spent on near work and time spent outdoors, neither the genotypes nor the allele frequencies of the three SNPs were significantly associated with myopic shift, incident myopia or the change in SER. After adjusting for age, sex, near-work time and outdoor time with 10,000 permutations, the genotype AREG (rs12511037) was associated with an increase in AL (P'-values for the dominant, recessive, additive and general models were 0.0032, 0.0275, 0.0045, and 0.0099, respectively); the genotype PDE10A (rs12206610) was associated with a change in CC in the additive (P' = 0.0096), dominant (P' = 0.0096), and heterozygous models (P' = 0.0096).ConclusionThese findings preliminarily indicate that AREG SNP rs12511037 and PDE10A SNP rs12206610 are etiologically relevant for ocular traits, providing a basis for further exploration of the development of myopia and its molecular mechanism. However, elucidating the role of AREG and PDE10A in the pathogenesis of myopia requires further animal model and human genetic epidemiology studies. This trial is registered as ChiCTR1900020584 at www.Chictr.org.cn.

Dataset Information

Genome-wide association meta-analysis of corneal curvature identifies novel loci and shared genetic influences across axial length and refractive error.

Publications

Genome-wide association meta-analysis of corneal curvature identifies novel loci and shared genetic influences across axial length and refractive error.

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