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Robert P. Igo, Christopher W. Halladay, Dana C. Crawford, Tamer Hadi, Paul B Greenberg, Jack Sullivan, Steven J. Fliesler, Wen-Chih Wu, P. Eric Konicki, Neal S. Peachey, Sudha K Iyengar; Evidence for novel risk loci for age-related macular degeneration on the X chromosome: the VA Million Veteran Program. Invest. Ophthalmol. Vis. Sci. 2019;60(9):2958.
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Genes on the X chromosome play a role in diseases of the retina, but thus far no X-linked risk factors for age-related macular degeneration (AMD) have been discovered by genomewide association studies. The Million Veteran Program (MVP) comprises one of the world’s most successful biobanks, with genotypes available for > 480K participants, most of whom are men. Using individual survey data and electronic health records (EHR) from the MVP, we conducted a male-specific X-chromosome association analysis for AMD, the results of which are more readily interpreted than an analysis including both men and women.
The MVP sample was genotyped for a custom Affymetrix Biobank chip including about 725,000 genome-wide genetic variants. We selected male Veterans > 50 years of age, who had ICD9/ICD10 codes for AMD from at least two eye clinic visits, as AMD cases, and male Veterans > 65 years of age with no AMD codes or no eye clinic visits as AMD controls. We carried out association analysis on 9,355 common, X-linked DNA variants (minor allele frequency ≥ 0.5%) in European American men (17,124 AMD cases and 136,053 controls) by logistic regression, adjusting for 10 principal components of population structure. The two pseudoautosomal regions at the termini of the X chromosome were omitted (human genome build GRCh37 regions < 2,699,645 and > 154,930,230 bp).
The Affymetrix Biobank panel yielded two major association peaks: near PRKX (rs111602303, OR = 1.094, p = 3.0 × 10–13) and a broad peak with chromosome-wide significant results (p < 5.3 × 10–6, Bonferroni adjusted for 9,355 tests) across a 3.2-megabasepair (Mb) region (88.9-92.1 Mb) with index SNP rs73535318 (OR = 1.72, p = 7.1 × 10–70). PRKX is a subunit of a developmentally regulated serine/threonine protein kinase that may be involved in fluid regulation and angiogenesis in the retina. The broad association region contains three protein-coding genes, TGIF2LX, PABPC5 and PCDH11X, and spans the X-transposed region, a region in Xq21.3 of high similarity between X and Y chromosomes. PCDH11X, a member of the cadherin superfamily, may be involved in the development of the central nervous system.
We have identified two novel potential AMD risk loci with moderate effect on the X chromosome in US Veterans, the largest male-only cohort studied to date.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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