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Genome-wide meta-analyses of multiancestry cohorts identify multiple new susceptibility loci for refractive error and myopia.

ABSTRACT: Refractive error is the most common eye disorder worldwide and is a prominent cause of blindness. Myopia affects over 30% of Western populations and up to 80% of Asians. The CREAM consortium conducted genome-wide meta-analyses, including 37,382 individuals from 27 studies of European ancestry and 8,376 from 5 Asian cohorts. We identified 16 new loci for refractive error in individuals of European ancestry, of which 8 were shared with Asians. Combined analysis identified 8 additional associated loci. The new loci include candidate genes with functions in neurotransmission (GRIA4), ion transport (KCNQ5), retinoic acid metabolism (RDH5), extracellular matrix remodeling (LAMA2 and BMP2) and eye development (SIX6 and PRSS56). We also confirmed previously reported associations with GJD2 and RASGRF1. Risk score analysis using associated SNPs showed a tenfold increased risk of myopia for individuals carrying the highest genetic load. Our results, based on a large meta-analysis across independent multiancestry studies, considerably advance understanding of the mechanisms involved in refractive error and myopia.

SUBMITTER: Verhoeven VJ

PROVIDER: S-EPMC3740568 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Genome-wide meta-analyses of multiancestry cohorts identify multiple new susceptibility loci for refractive error and myopia.

Verhoeven Virginie J M VJ Hysi Pirro G PG Wojciechowski Robert R Fan Qiao Q Guggenheim Jeremy A JA Höhn René R MacGregor Stuart S Hewitt Alex W AW Nag Abhishek A Cheng Ching-Yu CY Yonova-Doing Ekaterina E Zhou Xin X Ikram M Kamran MK Buitendijk Gabriëlle H S GH McMahon George G Kemp John P JP Pourcain Beate St BS Simpson Claire L CL Mäkelä Kari-Matti KM Lehtimäki Terho T Kähönen Mika M Paterson Andrew D AD Hosseini S Mohsen SM Wong Hoi Suen HS Xu Liang L Jonas Jost B JB Pärssinen Olavi O Wedenoja Juho J Yip Shea Ping SP Ho Daniel W H DW Pang Chi Pui CP Chen Li Jia LJ Burdon Kathryn P KP Craig Jamie E JE Klein Barbara E K BE Klein Ronald R Haller Toomas T Metspalu Andres A Khor Chiea-Chuen CC Tai E-Shyong ES Aung Tin T Vithana Eranga E Tay Wan-Ting WT Barathi Veluchamy A VA Chen Peng P Li Ruoying R Liao Jiemin J Zheng Yingfeng Y Ong Rick T RT Döring Angela A Evans David M DM Timpson Nicholas J NJ Verkerk Annemieke J M H AJ Meitinger Thomas T Raitakari Olli O Hawthorne Felicia F Spector Tim D TD Karssen Lennart C LC Pirastu Mario M Murgia Federico F Ang Wei W Mishra Aniket A Montgomery Grant W GW Pennell Craig E CE Cumberland Phillippa M PM Cotlarciuc Ioana I Mitchell Paul P Wang Jie Jin JJ Schache Maria M Janmahasatian Sarayut S Igo Robert P RP Lass Jonathan H JH Chew Emily E Iyengar Sudha K SK Gorgels Theo G M F TG Rudan Igor I Hayward Caroline C Wright Alan F AF Polasek Ozren O Vatavuk Zoran Z Wilson James F JF Fleck Brian B Zeller Tanja T Mirshahi Alireza A Müller Christian C Uitterlinden André G AG Rivadeneira Fernando F Vingerling Johannes R JR Hofman Albert A Oostra Ben A BA Amin Najaf N Bergen Arthur A B AA Teo Yik-Ying YY Rahi Jugnoo S JS Vitart Veronique V Williams Cathy C Baird Paul N PN Wong Tien-Yin TY Oexle Konrad K Pfeiffer Norbert N Mackey David A DA Young Terri L TL van Duijn Cornelia M CM Saw Seang-Mei SM Bailey-Wilson Joan E JE Stambolian Dwight D Klaver Caroline C CC Hammond Christopher J CJ

Nature genetics 20130210 3

Refractive error is the most common eye disorder worldwide and is a prominent cause of blindness. Myopia affects over 30% of Western populations and up to 80% of Asians. The CREAM consortium conducted genome-wide meta-analyses, including 37,382 individuals from 27 studies of European ancestry and 8,376 from 5 Asian cohorts. We identified 16 new loci for refractive error in individuals of European ancestry, of which 8 were shared with Asians. Combined analysis identified 8 additional associated l ...[more]

PMID: 23396134

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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

Genome-wide meta-analyses of multiancestry cohorts identify multiple new susceptibility loci for refractive error and myopia.

Publications

Genome-wide meta-analyses of multiancestry cohorts identify multiple new susceptibility loci for refractive error and myopia.

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