Exome genotyping and linkage analysis identifies two novel linked regions and replicates two others for myopia in Ashkenazi Jewish families

Claire L Simpson,Laura Portas,Federico Murgia,Emily R Holzinger,Joan E Bailey-Wilson,Anthony M Musolf,Candace D Middlebrooks,Bilal A Moiz,Jennifer B Cordero,Dwight Stambolian,Qing Li,Deyana D Lewis,Roberto Y Cordero

doi:10.1186/s12881-019-0752-8

Abstract

BackgroundMyopia is one of most common eye diseases in the world and affects 1 in 4 Americans. It is a complex disease caused by both environmental and genetics effects; the genetics effects are still not well understood. In this study, we performed genetic linkage analyses on Ashkenazi Jewish families with a strong familial history of myopia to elucidate any potential causal genes.MethodsSixty-four extended Ashkenazi Jewish families were previously collected from New Jersey. Genotypes from the Illumina ExomePlus array were merged with prior microsatellite linkage data from these families. Additional custom markers were added for candidate regions reported in literature for myopia or refractive error. Myopia was defined as mean spherical equivalent (MSE) of -1D or worse and parametric two-point linkage analyses (using TwoPointLods) and multi-point linkage analyses (using SimWalk2) were performed as well as collapsed haplotype pattern (CHP) analysis in SEQLinkage and association analyses performed with FBAT and rv-TDT.ResultsStrongest evidence of linkage was on 1p36(two-point LOD = 4.47) a region previously linked to refractive error (MYP14) but not myopia. Another genome-wide significant locus was found on 8q24.22 with a maximum two-point LOD score of 3.75. CHP analysis also detected the signal on 1p36, localized to the LINC00339 gene with a maximum HLOD of 3.47, as well as genome-wide significant signals on 7q36.1 and 11p15, which overlaps with the MYP7 locus.ConclusionsWe identified 2 novel linkage peaks for myopia on chromosomes 7 and 8 in these Ashkenazi Jewish families and replicated 2 more loci on chromosomes 1 and 11, one previously reported in refractive error but not myopia in these families and the other locus previously reported in the literature. Strong candidate genes have been identified within these linkage peaks in our families. Targeted sequencing in these regions will be necessary to definitively identify causal variants under these linkage peaks.

Highlights

Myopia is one of most common eye diseases in the world and affects 1 in 4 Americans
Whole exome sequencing (WES) has been used in a number of traits to identify causal variants that modify the risk of developing traits and diseases and this can be an attractive approach in phenotypes that are relatively uncommon, the challenges for identifying which variants are truly causal in a common trait like myopia are much greater
Family-based linkage studies using sparse panels of genetic markers (microsatellites and common single nucleotide polymorphisms (SNPs)) have identified regions of the genome likely to be harboring high-risk rare variants contributing to non-pathogenic myopia (MSE < −1D) in highly aggregated families [13,14,15,16,17,18,19,20,21,22] but the causal variants responsible for these results have not yet been identified

Summary

Introduction

Myopia is one of most common eye diseases in the world and affects 1 in 4 Americans. It is a complex disease caused by both environmental and genetics effects; the genetics effects are still not well understood. Family-based study designs have several advantages over population-based studies, especially when focusing on rare variants, as these may be enriched within a family even if they are rare in the population and require lower numbers of individuals to retain sufficient power. This approach has been used successfully to identify genes increasing risk for pathogenic or “high” myopia (mean spherical equivalent (MSE) < − 6 diopters (D)) [10,11,12].

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