Liao, Sha-Mei, Zheng, Wei, Lewis, Casey, Delgado, Omar, Crowley, Maura, Buchanan, Natasha, Jaffee, Bruce, Dryja, Ted and Zhu, Jiang (2017) Specific correlation between the chromosome 10q26 haplotype conferring high risk for age-related macular degeneration and the expression of HTRA1 in human tissues. Molecular vision :, 23. pp. 318-333. ISSN 1090-0535

Abstract

Purpose: A region within chromosome 10q26 has a set of SNPs in linkage disequilibrium (LD) and that defines a haplotype that confers high risk for age-related macular degeneration (AMD). We searched for genes in this region that may be responsible for AMD risk by assessing levels of gene expression in individuals carrying different haplotypes and by searching for open chromatin regions in retinal pigment epithelium that might include one of the SNPs.
Methods: We surveyed the PubMed and the 1000 Genomes databases to find all common (minor allele frequency > 0.01) SNPs in the 10q26 region strongly associated with AMD. We used the HaploReg database to search for linkage disequilibrium between SNPs. We surveyed the Genotype-Tissue Expression (GTEx) database to determine the level of expression of genes. For expression-quantitative trait loci (eQTL) analysis, we evaluated tissues for which high-quality mRNA results were available in at least 70 genotyped donors. The Encyclopedia of DNA Elements (ENCODE) was accessed to find segments of open chromatin in the region with the AMD-associated SNPs. Predicted transcription factor binding motifs were identified using HOMER and PROMO software programs.{Yamada, 2008 #136}
Results: There are 25 SNPs within a 30-kb region that are in LD (r2 > 0.8) with the reference SNP rs10490924 previously associated with risk for AMD. The expression of three genes in this region, ARMS2, HTRA1, and PLEKHA1, varies according to the haplotypes. For ARMS2, the variation is most pronounced in testes: homozygotes with the high-AMD-risk haplotype express ARMS2 at lower levels than homozygotes with the low-AMD-risk, with heterozygotes falling in between (effect size -0.79, p = 7.5 x 10-24). With regard to PLEKHA1, 44 tissues have an expression pattern similar to ARMS2 with the high-AMD-risk haplotype associated with low expression (rs10490924 effect size -0.43, p = 3.8 x 10-5 in ovary). For HTRA1, the expression pattern is opposite with the high-AMD-risk haplotype having higher levels of expression in 27 tissues (rs10490924 effect size 0.40, p = 1.5 x 10-7 in testis). None of the other 22 genes within one megabase of rs10490924, nor any gene in the entire genome, have patterns of mRNA expression levels that correlate with the high-AMD-risk haplotype. Many other SNPs in the 10q26 region affect the expression of ARMS2 and PLEKHA1, but none of these additional SNPS have been reported to affect the risk for AMD in published GWAS. The SNPs rs36212732 and rs36212733, which are in strong linkage disequilibrium with the known AMD-risk SNP rs10490924 (r2 = 1), are within a DNAse I hypersensitive region (i.e., a region of open chromatin) in retinal pigment epithelial cells. This presumably open chromatin region might be the site of transcription factors that mediate the variation HTRA1 expression.
Conclusions/Discussions: The variation in AMD risk associated with SNPS in chromosome 10q26 is most likely due to variation in HTRA1 expression. Modulating HTRA1 activity might be a potential therapy for AMD.

Item Type:	Article
Date Deposited:	19 Jul 2017 00:45
Last Modified:	19 Jul 2017 00:45
URI:	https://oak.novartis.com/id/eprint/31518