Abstract
Purpose: :
We performed genomewide linkage scans in African American (AA), Ashkenazi Jewish (ASHK), Caucasian (CAUC), Old Order Amish (OOA) families to identify genomic regions containing genes responsible for refractive error variation. We also performed a meta-analysis by combining pointwise linkage results across the populations.
Methods: :
We recruited 493 AA, 542 ASHK, 271 CAUC and 411 OOA, subjects (in 96, 49, 36 and 61 families, respectively) to participate in the Myopia Family Study. Recruitment criteria were designed to enrich the sample for multiplex myopic families. The mean spherical equivalent (MSE) refractions were: -2.86D (AA), -2.90D (ASHK),-2.90D (CAUC) and -1.69D (OOA). Genotyping was performed using >370 autosomal microsatellite markers. MSE refractions were log-transformed prior to quantitative-trait linkage analysis. Genomewide multipoint linkage analyses were conducted separately for each population using the extended regression-based method implemented in Merlin-regress. All population-specific significance levels were determined empirically via whole-genome gene-dropping simulations. Meta-analysis significance levels (meta-P) were estimated by combining pointwise linkage statistics from the AA, ASHK, CAUC and OOA families. Meta-analysis linkage peak locations were compared to previously-reported loci for myopia and ocular refraction.
Results: :
Genomewide-significant evidence of linkage to refraction was found at 1p36 (LOD=8.7, p<.0001) in ASHK, and 7p15 (LOD=5.87, p<.0001) in AA families. Suggestive evidence of linkage was found at 12q24 (LOD=4.583, P=.00037) in CAUC, and 5qter (LOD=3.271, P=.0014) in OOA. Meta-analysis results were largely driven by population-specific linkage peaks, with the highest signals (at: 1p36, meta-P=.0003; and 7p15, meta-P=.0013) corresponding to loci identified in single-population analyses. The meta-analysis also showed suggestive evidence of linkage to a region on chr.4q21-22 (meta-P=0.0021) adjacent to the previously-reported MYP9 and MYP11 loci.
Conclusions: :
We found evidence of linkage of ocular refraction to different loci in four ethnically defined populations. Our meta-analysis results support a role for a locus on chr4q in refractive variation across populations. However, our analyses suggest that several genes play a role in human refractive development, confirming the complex nature of the genetic control of ocular refraction.
Keywords: linkage analysis • gene mapping • myopia