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Rare variants and loci for age-related macular degeneration in the Ohio and Indiana Amish.

ABSTRACT: Age-related macular degeneration (AMD) is a leading cause of blindness in the world. While dozens of independent genomic variants are associated with AMD, about one-third of AMD heritability is still unexplained. To identify novel variants and loci for AMD, we analyzed Illumina HumanExome chip data from 87 Amish individuals with early or late AMD, 79 unaffected Amish individuals, and 15 related Amish individuals with unknown AMD affection status. We retained 37,428 polymorphic autosomal variants across 175 samples for association and linkage analyses. After correcting for multiple testing (n?=?37,428), we identified four variants significantly associated with AMD: rs200437673 (LCN9, p?=?1.50?×?10-11), rs151214675 (RTEL1, p?=?3.18?×?10-8), rs140250387 (DLGAP1, p?=?4.49?×?10-7), and rs115333865 (CGRRF1, p?=?1.05?×?10-6). These variants have not been previously associated with AMD and are not in linkage disequilibrium with the 52 known AMD-associated variants reported by the International AMD Genomics Consortium based on physical distance. Genome-wide significant linkage peaks were observed on chromosomes 8q21.11-q21.13 (maximum recessive HLOD?=?4.03) and 18q21.2-21.32 (maximum dominant HLOD?=?3.87; maximum recessive HLOD?=?4.27). These loci do not overlap with loci previously linked to AMD. Through gene ontology enrichment analysis with ClueGO in Cytoscape, we determined that several genes in the 1-HLOD support interval of the chromosome 8 locus are involved in fatty acid binding and triglyceride catabolic processes, and the 1-HLOD support interval of the linkage region on chromosome 18 is enriched in genes that participate in serine-type endopeptidase inhibitor activity and the positive regulation of epithelial to mesenchymal transition. These results nominate novel variants and loci for AMD that require further investigation.

SUBMITTER: Waksmunski AR

PROVIDER: S-EPMC6745026 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Rare variants and loci for age-related macular degeneration in the Ohio and Indiana Amish.

Waksmunski Andrea R AR Igo Robert P RP Song Yeunjoo E YE Cooke Bailey Jessica N JN Laux Renee R Fuzzell Denise D Fuzzell Sarada S Adams Larry D LD Caywood Laura L Prough Michael M Stambolian Dwight D Scott William K WK Pericak-Vance Margaret A MA Haines Jonathan L JL

Human genetics 20190731 10

Age-related macular degeneration (AMD) is a leading cause of blindness in the world. While dozens of independent genomic variants are associated with AMD, about one-third of AMD heritability is still unexplained. To identify novel variants and loci for AMD, we analyzed Illumina HumanExome chip data from 87 Amish individuals with early or late AMD, 79 unaffected Amish individuals, and 15 related Amish individuals with unknown AMD affection status. We retained 37,428 polymorphic autosomal variants ...[more]

PMID: 31367973

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Project description:PurposeGenetic variants in the complement factor H gene (CFH) have been consistently implicated in age-related macular degeneration (AMD) risk. However, their functional effects are not fully characterized. We previously identified a rare, AMD-associated variant in CFH (P503A, rs570523689) in 19 Amish individuals, but its functional consequences were not investigated.MethodsWe performed genotyping for CFH P503A in 1326 Amish individuals to identify additional risk allele carriers. We examined differences for age at AMD diagnosis between carriers and noncarriers. In blood samples from risk allele carriers and noncarriers, we quantified (i) CFH RNA expression, (ii) CFH protein expression, and (iii) C-reactive protein (CRP) expression. Potential changes to the CFH protein structure were interrogated computationally with Phyre2 and Chimera software programs.ResultsWe identified 39 additional carriers from Amish communities in Ohio and Indiana. On average, carriers were younger than noncarriers at AMD diagnosis, but this difference was not significant. CFH transcript and protein levels in blood samples from Amish carriers and noncarriers were also not significantly different. CRP levels were also comparable in plasma samples from carriers and noncarriers. Computational protein modeling showed slight changes in the CFH protein conformation that were predicted to alter interactions between the CFH 503 residue and other neighboring residues.ConclusionsIn total, we have identified 58 risk allele carriers for CFH P503A in the Ohio and Indiana Amish. Although we did not detect significant differences in age at AMD diagnosis or expression levels of CFH in blood samples from carriers and noncarriers, we observed modest structural changes to the CFH protein through in silico modeling. Based on our functional and computational observations, we hypothesize that CFH P503A may affect CFH binding or function rather than expression, which would require additional research to confirm.

Dataset Information

Rare variants and loci for age-related macular degeneration in the Ohio and Indiana Amish.

Publications

Rare variants and loci for age-related macular degeneration in the Ohio and Indiana Amish.

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