African-American families show genome-wide significant linkage to myopia at 7p15.2-14.2

Abstract

Purpose : Myopia is the most common visual disease in the world and has reached epidemic proportions in some regions of the world. Yet, there is still much we do not know about the genetic causes of myopia. Here, we perform a genetic linkage study using African-American (AA) families with a history of myopia. The goal is to find genetic linkage between a genetic variant and myopia.

Methods : We have collected genetic and phenotypic data from 107 AA families from Philadelphia. We merged SNP data from an Illumina exome array with previous microsatellite data. Phenotypes were coded as either affected with myopia, unaffected, or unknown. We performed both variant-based and gene-based parametric linkage analyses. Variant-based analysis tested for linkage between myopia and a SNP or microsatellite. Gene-based analysis created a multiallelic pseudomarker corresponding to a gene from the haplotypes of rare variants within the gene. Linkage analysis was then performed between the phenotype and the gene-based pseudomarker. All analyses assumed an autosomal dominant model with disease allele frequency of 0.01 with 90% penetrance for carriers and 1% for non-carriers.

Results : The gene-based and variant-based analysis identified genome-wide significant linkage to the 7p15.2-14.2 region. This finding strengthens and narrows a previous linkage signal found in these AA families at 7p15. The top overall HLOD score in both analyses was above 4, a very significant linkage. The fact that the gene-based analysis (which contained rare variants) was so highly significant is especially promising, as a rare variant would be more expected to have a large effect size. The region contains several excellent candidate genes, including BBS9. BBS proteins have been found to affect both retinal growth and degeneration in mice.

Conclusions : We have identified a genome-wide significant genetic linkage for myopia at 7p15.2-14.2 in AA families. As this study was performed using exome-based array genotypes, we are currently unable to resolve the causal variant(s) within this region. We have planned targeted sequencing of the entire region in our most strongly linked families to identify the cause of the genetic linkage.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.