Specific correlation between the major chromosome 10q26 haplotype conferring risk for age-related macular degeneration and the expression of .

PURPOSE

A region within chromosome 10q26 has a set of single nucleotide polymorphisms (SNPs) that define a haplotype that confers high risk for age-related macular degeneration (AMD). We used a bioinformatics approach to search for genes in this region that may be responsible for risk for AMD by assessing levels of gene expression in individuals carrying different haplotypes and by searching for open chromatin regions in the retinal pigment epithelium (RPE) that might include one or more of the SNPs.

METHODS

We surveyed the PubMed and the 1000 Genomes databases to find all common (minor allele frequency > 0.01) SNPs in 10q26 strongly associated with AMD. We used the HaploReg and LDlink databases to find sets of SNPs with alleles in linkage disequilibrium and used the Genotype-Tissue Expression (GTEx) database to search for correlations between genotypes at individual SNPs and the relative level of expression of the genes. We also accessed Encyclopedia of DNA Elements (ENCODE) to find segments of open chromatin in the region with the AMD-associated SNPs. Predicted transcription factor binding motifs were identified using HOMER, PROMO, and RegulomeDB software programs.

RESULTS

There are 34 polymorphisms within a 30-kb region that are in strong linkage disequilibrium (r>0.8) with the reference SNP rs10490924 previously associated with risk for AMD. The expression of three genes in this region, , , and varies between people who have the low-AMD-risk haplotype compared with those with the high-AMD-risk haplotype. For , 44 tissues have an expression pattern with the high-AMD-risk haplotype associated with low expression (rs10490924 effect size -0.43, p = 3.8 x 10 in ovary). With regard to , the variation is most pronounced in testes: homozygotes with the high-AMD-risk haplotype express at lower levels than homozygotes with the low-AMD-risk haplotype; expression in heterozygotes falls in between (rs10490924 effect size -0.79, p = 7.5 x 10). For , the expression pattern is the opposite; the high-AMD-risk haplotype has higher levels of expression in 27 tissues (rs10490924 effect size 0.40, p = 1.5 × 10 in testes). None of the other 22 genes within one megabase of rs10490924, or any gene in the entire genome, have mRNA expression levels that correlate with the high-AMD-risk haplotype. More than 100 other SNPs in the 10q26 region affect the expression of and but not that of ; none of these SNPs affects the risk for AMD according to published genome-wide association studies (GWASs). Two of the AMD-risk SNPs (rs36212732 and rs36212733) affect transcription factor binding sites in proximity to a DNase I hypersensitive region (i.e., a region of open chromatin) in RPE cells.

CONCLUSIONS

SNPs in chromosome 10q26 that influence the expression of only or are not associated with risk for AMD, while most SNPs that influence the expression of are associated with risk for AMD. Two of the AMD-risk SNPs affect transcription factor binding sites that may control expression of one of the linked genes in the RPE. These findings suggest that the variation in the risk for AMD associated with chromosome 10q26 is likely due to variation in expression. Modulating activity might be a potential therapy for AMD.