Dataset Information

Specific correlation between the major chromosome 10q26 haplotype conferring risk for age-related macular degeneration and the expression of HTRA1.

ABSTRACT: 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.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.There are 34 polymorphisms within a 30-kb region that are in strong linkage disequilibrium (r2>0.8) with the reference SNP rs10490924 previously associated with risk for AMD. The expression of three genes in this region, PLEKHA1, ARMS2, and HTRA1 varies between people who have the low-AMD-risk haplotype compared with those with the high-AMD-risk haplotype. For PLEKHA1, 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 10-5 in ovary). With regard to 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 haplotype; expression in heterozygotes falls in between (rs10490924 effect size -0.79, p = 7.5 x 10-24). For HTRA1, 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 × 10-7 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 PLEKHA1 and ARMS2 but not that of HTRA1; 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.SNPs in chromosome 10q26 that influence the expression of only PLEKHA1 or ARMS2 are not associated with risk for AMD, while most SNPs that influence the expression of HTRA1 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 HTRA1 expression. Modulating HTRA1 activity might be a potential therapy for AMD.

SUBMITTER: Liao SM

PROVIDER: S-EPMC5479693 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Specific correlation between the major chromosome 10q26 haplotype conferring risk for age-related macular degeneration and the expression of <i>HTRA1</i>.

Liao Sha-Mei SM Zheng Wei W Zhu Jiang J Lewis Casey A CA Delgado Omar O Crowley Maura A MA Buchanan Natasha M NM Jaffee Bruce D BD Dryja Thaddeus P TP

Molecular vision 20170614

<h4>Purpose</h4>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 ...[more]

PMID: 28659708

Similar Datasets

Project description:BackgroundSingle-variant associations with age-related macular degeneration (AMD), one of the most prevalent causes of irreversible vision loss worldwide, have been studied extensively. However, because of a lack of refinement of these associations, there remains considerable ambiguity regarding what constitutes genetic risk and/or protection for this disease, and how genetic combinations affect this risk. In this study, we consider the two most common and strongly AMD-associated loci, the CFH-CFHR5 region on chromosome 1q32 (Chr1 locus) and ARMS2/HTRA1 gene on chromosome 10q26 (Chr10 locus).ResultsBy refining associations within the CFH-CFHR5 locus, we show that all genetic protection against the development of AMD in this region is described by the combination of the amino acid-altering variant CFH I62V (rs800292) and genetic deletion of CFHR3/1. Haplotypes based on CFH I62V, a CFHR3/1 deletion tagging SNP and the risk variant CFH Y402H are associated with either risk, protection or neutrality for AMD and capture more than 99% of control- and case-associated chromosomes. We find that genetic combinations of CFH-CFHR5 haplotypes (diplotypes) strongly influence AMD susceptibility and that individuals with risk/protective diplotypes are substantially protected against the development of disease. Finally, we demonstrate that AMD risk in the ARMS2/HTRA1 locus is also mitigated by combinations of CFH-CFHR5 haplotypes, with Chr10 risk variants essentially neutralized by protective CFH-CFHR5 haplotypes.ConclusionsOur study highlights the importance of considering protective CFH-CFHR5 haplotypes when assessing genetic susceptibility for AMD. It establishes a framework that describes the full spectrum of AMD susceptibility using an optimal set of single-nucleotide polymorphisms with known functional consequences. It also indicates that protective or preventive complement-directed therapies targeting AMD driven by CFH-CFHR5 risk haplotypes may also be effective when AMD is driven by ARMS2/HTRA1 risk variants.

Project description:BACKGROUND: Age-related macular degeneration (AMD) is the major cause of blindness in the elderly. Those with the neovascular end-stage of disease have irreversible loss of central vision. AMD is a complex disorder in which genetic and environmental factors play a role. Polymorphisms in the complement factor H (CFH) gene, LOC387715, and the HTRA1 promoter are strongly associated with AMD. Smoking also contributes to the etiology. We aimed to provide a model of disease risk based on these factors. METHODS AND FINDINGS: We genotyped polymorphisms in CFH and LOC387715/HTRA1 in a case-control study of 401 patients with neovascular AMD and 266 controls without signs of disease, and used the data to produce genetic risk scores for the European-descent population based on haplotypes at these loci and smoking history. CFH and LOC387715/HTRA1 haplotypes and smoking status exerted large effects on AMD susceptibility, enabling risk scores to be generated with appropriate weighting of these three factors. Five common haplotypes of CFH conferred a range of odds ratios (ORs) per copy from 1 to 4.17. Most of the effect of LOC387715/HTRA1 was mediated through one detrimental haplotype (carriage of one copy: OR 2.83; 95% confidence interval [CI] 1.91-4.20), with homozygotes being at particularly high risk (OR 32.83; 95% CI 12.53-86.07). Patients with neovascular macular degeneration had considerably higher scores than those without disease, and risk of blinding AMD rose to 15.5% in the tenth of the population with highest predicted risk. CONCLUSIONS: An individual's risk of developing AMD in old age can be predicted by combining haplotype data with smoking status. Until there is effective treatment for AMD, encouragement to avoid smoking in those at high genetic risk may be the best option. We estimate that total absence of smoking would have reduced the prevalence of severe AMD by 33%. Unless smoking habits change or preventative treatment becomes available, the prevalence of AMD will rise as a consequence of the increasing longevity of the population.

Dataset Information

Specific correlation between the major chromosome 10q26 haplotype conferring risk for age-related macular degeneration and the expression of HTRA1.

Publications

Specific correlation between the major chromosome 10q26 haplotype conferring risk for age-related macular degeneration and the expression of <i>HTRA1</i>.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets