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Meta-analysis of 542,934 subjects of European ancestry identifies new genes and mechanisms predisposing to refractive error and myopia.

ABSTRACT: Refractive errors, in particular myopia, are a leading cause of morbidity and disability worldwide. Genetic investigation can improve understanding of the molecular mechanisms that underlie abnormal eye development and impaired vision. We conducted a meta-analysis of genome-wide association studies (GWAS) that involved 542,934 European participants and identified 336 novel genetic loci associated with refractive error. Collectively, all associated genetic variants explain 18.4% of heritability and improve the accuracy of myopia prediction (area under the curve (AUC) = 0.75). Our results suggest that refractive error is genetically heterogeneous, driven by genes that participate in the development of every anatomical component of the eye. In addition, our analyses suggest that genetic factors controlling circadian rhythm and pigmentation are also involved in the development of myopia and refractive error. These results may enable the prediction of refractive error and the development of personalized myopia prevention strategies in the future.

SUBMITTER: Hysi PG

PROVIDER: S-EPMC7145443 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Meta-analysis of 542,934 subjects of European ancestry identifies new genes and mechanisms predisposing to refractive error and myopia.

Hysi Pirro G PG Choquet Hélène H Khawaja Anthony P AP Wojciechowski Robert R Tedja Milly S MS Yin Jie J Simcoe Mark J MJ Patasova Karina K Mahroo Omar A OA Thai Khanh K KK Cumberland Phillippa M PM Melles Ronald B RB Verhoeven Virginie J M VJM Vitart Veronique V Segre Ayellet A Stone Richard A RA Wareham Nick N Hewitt Alex W AW Mackey David A DA Klaver Caroline C W CCW MacGregor Stuart S Khaw Peng T PT Foster Paul J PJ Guggenheim Jeremy A JA Rahi Jugnoo S JS Jorgenson Eric E Hammond Christopher J CJ

Nature genetics 20200330 4

Refractive errors, in particular myopia, are a leading cause of morbidity and disability worldwide. Genetic investigation can improve understanding of the molecular mechanisms that underlie abnormal eye development and impaired vision. We conducted a meta-analysis of genome-wide association studies (GWAS) that involved 542,934 European participants and identified 336 novel genetic loci associated with refractive error. Collectively, all associated genetic variants explain 18.4% of heritability a ...[more]

PMID: 32231278

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Project description:Refractive error (RE) and myopia are complex polygenic conditions with the majority of genome-wide associated genetic variants in non-exonic regions. Given this, and the onset during childhood, gene-regulation is expected to play an important role in its pathogenesis. This prompted us to explore beyond traditional gene finding approaches. We performed a genetic association study between variants in non-coding RNAs and enhancers, and RE and myopia. We obtained single-nucleotide polymorphisms (SNPs) in microRNA (miRNA) genes, miRNA-binding sites, long non-coding RNAs genes (lncRNAs) and enhancers from publicly available databases: miRNASNPv2, PolymiRTS, VISTA Enhancer Browser, FANTOM5 and lncRNASNP2. We investigated whether SNPs overlapping these elements were associated with RE and myopia leveraged from a large GWAS meta-analysis (N = 160,420). With genetic risk scores (GRSs) per element, we investigated the joint effect of associated variants on RE, axial length (AL)/corneal radius (CR), and AL progression in an independent child cohort, the Generation R Study (N = 3638 children). We constructed a score for biological plausibility per SNP in highly confident miRNA-binding sites and enhancers in chromatin accessible regions. We found that SNPs in two miRNA genes, 14 enhancers and 81 lncRNA genes in chromatin accessible regions and 54 highly confident miRNA-binding sites, were in RE and myopia-associated loci. GRSs from SNPs in enhancers were significantly associated with RE, AL/CR and AL progression. GRSs from lncRNAs were significantly associated with all AL/CR and AL progression. GRSs from miRNAs were not associated with any ocular biometric measurement. GRSs from miRNA-binding sites showed suggestive but inconsistent significance. We prioritized candidate miRNA binding sites and candidate enhancers for future functional validation. Pathways of target and host genes of highly ranked variants included eye development (BMP4, MPPED2), neurogenesis (DDIT4, NTM), extracellular matrix (ANTXR2, BMP3), photoreceptor metabolism (DNAJB12), photoreceptor morphogenesis (CHDR1), neural signaling (VIPR2) and TGF-beta signaling (ANAPC16). This is the first large-scale study of non-coding RNAs and enhancers for RE and myopia. Enhancers and lncRNAs could be of large importance as they are associated with childhood myopia. We provide a confident blueprint for future functional validation by prioritizing candidate miRNA binding sites and candidate enhancers.

Dataset Information

Meta-analysis of 542,934 subjects of European ancestry identifies new genes and mechanisms predisposing to refractive error and myopia.

Publications

Meta-analysis of 542,934 subjects of European ancestry identifies new genes and mechanisms predisposing to refractive error and myopia.

Similar Datasets

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