Myopia in African Americans Is Significantly Linked to Chromosome 7p15.2-14.2

Abstract

Purpose: The purpose of this study was to perform genetic linkage analysis and association analysis on exome genotyping from highly aggregated African American families with nonpathogenic myopia. African Americans are a particularly understudied population with respect to myopia.

Methods: One hundred six African American families from the Philadelphia area with a family history of myopia were genotyped using an Illumina ExomePlus array and merged with previous microsatellite data. Myopia was initially measured in mean spherical equivalent (MSE) and converted to a binary phenotype where individuals were identified as affected, unaffected, or unknown. Parametric linkage analysis was performed on both individual variants (single-nucleotide polymorphisms [SNPs] and microsatellites) as well as gene-based markers. Family-based association analysis and transmission disequilibrium test (TDT) analysis modified for rare variants was also performed.

Results: Genetic linkage analysis identified 2 genomewide significant variants at 7p15.2 and 7p14.2 (in the intergenic region between MIR148A and NFE2L3 and in the noncoding RNA LOC401324) and 2 genomewide significant genes (CRHR2 and AVL9) both at 7p14.3. No genomewide results were found in the association analyses.

Conclusions: This study identified a significant linkage peak in African American families for myopia at 7p15.2 to 7p14.2, the first potential risk locus for myopia in African Americans. Interesting candidate genes are located in the region, including PDE1C, which is highly expressed in the eyes, and known to be involved in retinal development. Further identification of the causal variants at this linkage peak will help elucidate the genetics of myopia in this understudied population.

Figure 1.

HLOD scores for variant-based two-point linkage analysis. (A) The genomewide HLOD scores (B) the HLOD scores for chromosome 7. In both, the lines at 3.3 and 1.9 represent the respective significant and suggestive thresholds as suggested by Lander and Kruglyak.

Figure 2.

Genome wide HLODs scores for gene-based two-point linkage analysis. (A) The gene-based HLOD scores using only the rare variants (MAF ≤ 0.05) and (B) the gene-based HLOD scores using all variants. The lines at 3.3 and 1.9 represent the respective significant and suggestive thresholds as suggested by Lander and Kruglyak.

Figure 3.

Pan-human tissue differential expression of ANLN, FAM126A, MPP6, PDE1C, EPHB2, and ZNF462. The x-axis shows the different types of tissues used in the test. The y-axis shows the log2 fold change of gene expression. The differential expression is being shown relative to the reference tissue (whole blood).

Figure 4.

Pan-human tissue differential expression of additional significant and suggestive genes in the two-point linkage analysis. The x-axis shows the different types of tissues used in the test. The y-axis shows the log2 fold change of gene expression. The differential expression is being shown relative to the reference tissue (whole blood).