Replication of known loci and suggestive linkage for Familial Myopia on three chromosomes in African-Americans

Abstract

Purpose : Populations of African descent have lower rates of myopia than other populations, but multiplex families from the African-American (AA) population may represent an opportunity to identify unique susceptibility and protective alleles. Prior analyses of these families with a microsatellite linkage panel found significant evidence of linkage of refractive error to 7p15. Here we present linkage analyses of exome array data in AA myopia families.

Methods : Genotype data from the Illumina exome array was merged with genome-wide microsatellite data from a previous study on 107 multiplex AA families from the Philadelphia area. We performed both two-point (MCLink) and multi-point (SimWalk) parametric linkage analyses using myopia defined as a mean spherical equivalent (MSE) of -1D or worse.

Results : A number of variants in the 7p15 region had HLOD scores in the significant range, with a genome-wide significant max HLOD of 4.35. Suggestive replication of prior loci for myopia was found for MYP14 (1p36, max LOD=1.95), MYP16 (5p15.2, max LOD=1.99) and MYP2 (18p11.31, max LOD=2.16). Individual family LOD scores revealed several areas of interest. The highest LODs came from an 8.6 Mb region on chromosome 12 in Family 5022: 23 suggestive LODs were found here; corroborated by both two-point and multi-point analyses. Several candidate genes exist in the region including ANO2, which may mediate light perception amplification in the retina and PRR4, which may have a protective function in the eye. The same family also had a suggestive peak in a 30.5 Mb region on chromosome 3 with the most promising candidate genes being FBLN2 (an extracellular matrix protein) and 3 genes involved in ubiquitin ligation/modification. Family 5017 also displayed suggestive linkage on 7q. We observed a fairly dense signal, with 15 variants having LODs above 1 in a small region (6.6 Mb). The region includes two miRNA genes.

Conclusions : We found significant evidence of linkage of myopia to a number of variants in the 7p15 region and also found evidence for replication at 3 more loci. We also found at least 3 suggestive candidate regions for myopia linkage in individual families. Several promising gene candidates have been identified in these regions, 2 on chromosome 12 that are known to function in the eye. Further elucidation of these signals will be performed via deep sequencing of the candidate regions.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.