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Meta-analysis of genome-wide association studies in five cohorts reveals common variants in RBFOX1, a regulator of tissue-specific splicing, associated with refractive error.

ABSTRACT: Visual refractive errors (REs) are complex genetic traits with a largely unknown etiology. To date, genome-wide association studies (GWASs) of moderate size have identified several novel risk markers for RE, measured here as mean spherical equivalent (MSE). We performed a GWAS using a total of 7280 samples from five cohorts: the Age-Related Eye Disease Study (AREDS); the KORA study ('Cooperative Health Research in the Region of Augsburg'); the Framingham Eye Study (FES); the Ogliastra Genetic Park-Talana (OGP-Talana) Study and the Multiethnic Study of Atherosclerosis (MESA). Genotyping was performed on Illumina and Affymetrix platforms with additional markers imputed to the HapMap II reference panel. We identified a new genome-wide significant locus on chromosome 16 (rs10500355, P = 3.9 × 10(-9)) in a combined discovery and replication set (26 953 samples). This single nucleotide polymorphism (SNP) is located within the RBFOX1 gene which is a neuron-specific splicing factor regulating a wide range of alternative splicing events implicated in neuronal development and maturation, including transcription factors, other splicing factors and synaptic proteins.

SUBMITTER: Stambolian D

PROVIDER: S-EPMC3674806 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Meta-analysis of genome-wide association studies in five cohorts reveals common variants in RBFOX1, a regulator of tissue-specific splicing, associated with refractive error.

Stambolian Dwight D Wojciechowski Robert R Oexle Konrad K Pirastu Mario M Li Xiaohui X Raffel Leslie J LJ Cotch Mary Frances MF Chew Emily Y EY Klein Barbara B Klein Ronald R Wong Tien Y TY Simpson Claire L CL Klaver Caroline C W CC van Duijn Cornelia M CM Verhoeven Virginie J M VJ Baird Paul N PN Vitart Veronique V Paterson Andrew D AD Mitchell Paul P Saw Seang Mei SM Fossarello Maurizio M Kazmierkiewicz Krista K Murgia Federico F Portas Laura L Schache Maria M Richardson Andrea A Xie Jing J Wang Jie Jin JJ Rochtchina Elena E Viswanathan Ananth C AC Hayward Caroline C Wright Alan F AF Polasek Ozren O Campbell Harry H Rudan Igor I Oostra Ben A BA Uitterlinden André G AG Hofman Albert A Rivadeneira Fernando F Amin Najaf N Karssen Lennart C LC Vingerling Johannes R JR Hosseini S M SM Döring Angela A Bettecken Thomas T Vatavuk Zoran Z Gieger Christian C Wichmann H-Erich HE Wilson James F JF Fleck Brian B Foster Paul J PJ Topouzis Fotis F McGuffin Peter P Sim Xueling X Inouye Michael M Holliday Elizabeth G EG Attia John J Scott Rodney J RJ Rotter Jerome I JI Meitinger Thomas T Bailey-Wilson Joan E JE

Human molecular genetics 20130307 13

Visual refractive errors (REs) are complex genetic traits with a largely unknown etiology. To date, genome-wide association studies (GWASs) of moderate size have identified several novel risk markers for RE, measured here as mean spherical equivalent (MSE). We performed a GWAS using a total of 7280 samples from five cohorts: the Age-Related Eye Disease Study (AREDS); the KORA study ('Cooperative Health Research in the Region of Augsburg'); the Framingham Eye Study (FES); the Ogliastra Genetic Pa ...[more]

PMID: 23474815

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Project description:PurposeGenetic variants identified through population-based genome-wide studies are generally of high frequency, exerting their action in the central part of the refractive error spectrum. However, the power to identify associations with variants of lower minor allele frequency is greatly reduced, requiring considerable sample sizes. Here we aim to assess the impact of rare variants on genetic variation of refractive errors in a very large general population cohort.MethodsGenetic association analyses of non-cyclopaedic autorefraction calculated as mean spherical equivalent (SPHE) used whole-exome sequence genotypic information from 50,893 unrelated participants in the UK Biobank of European ancestry. Gene-based analyses tested for association with SPHE using an optimised SNP-set kernel association test (SKAT-O) restricted to rare variants (minor allele frequency < 1%) within protein-coding regions of the genome. All models were adjusted for age, sex and common lead variants within the same locus reported by previous genome-wide association studies. Potentially causal markers driving association at significant loci were elucidated using sensitivity analyses by sequentially dropping the most associated variants from gene-based analyses.ResultsWe found strong statistical evidence for association of SPHE with the SIX6 (p-value = 2.15 x 10-10, or Bonferroni-Corrected p = 4.41x10-06) and the CRX gene (p-value = 6.65 x 10-08, or Bonferroni-Corrected p = 0.001). The SIX6 gene codes for a transcription factor believed to be critical to the eye, retina and optic disc development and morphology, while CRX regulates photoreceptor specification and expression of over 700 genes in the retina. These novel associations suggest an important role of genes involved in eye morphogenesis in refractive error.ConclusionThe results of our study support previous research highlighting the importance of rare variants to the genetic risk of refractive error. We explain some of the origins of the genetic signals seen in GWAS but also report for the first time a completely novel association with the CRX gene.

Dataset Information

Meta-analysis of genome-wide association studies in five cohorts reveals common variants in RBFOX1, a regulator of tissue-specific splicing, associated with refractive error.

Publications

Meta-analysis of genome-wide association studies in five cohorts reveals common variants in RBFOX1, a regulator of tissue-specific splicing, associated with refractive error.

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