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

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.Electronic supplementary materialThe online version of this article (10.1186/s12881-019-0752-8) contains supplementary material, which is available to authorized users.

Rare variant analyses across multiethnic cohorts identify novel genes for refractive error

“…CMC betas were 0.1666, 0.1574, −0.1976, −0.1102, −0.518 for IECC, EACC, BDES, EPIC-Norfolk, and REHS respectively; none of the CMC p-values were significant, however (Supplementary Data 28). Circadian rhythm genes have been shown to be associated with refractive error 22 and PER3 is located near the site of a known myopia locus (MYP14) at which the causal gene has not been identified [37][38][39] . PER3 was expressed in ON and OFF bipolar cells.…”

IMI 2021 Yearly Digest

“…Two new studies have used this approach in families from 2 founder populations in the United States, the Pennsylvania Amish 102 and an orthodox Ashkenazi Jewish community. 103 In both studies, pedigrees with a strong family history of common myopia were enrolled, and exome-based microarray genotyping was performed. Participants underwent extensive eye examinations; myopia was defined as a mean spherical equivalent ≤ –1 D. An autosomal dominant model with a rare disease allele was assumed in the 2-point parametric linkage analyses.…”

The relationship between education levels, lifestyle, and religion regarding the prevalence of myopia in Israel

“…It is known that both genetics and environmental factors play a role in its development. On the one hand, some reports have shown that the role of genetics is more substantial in myopia development [ 3 , 4 ], as indicated by the discovery of a myopia susceptibility gene found by wide genome sequencing in the Ashkenazi Jewish population [ 5 , 6 ]. These mutations however have not yet been linked to myopia in Ultra-Orthodox communities.…”