Abstract
Primary open-angle glaucoma (POAG) is a leading cause of irreversible vision loss, yet much of the genetic risk remains unaccounted for, especially in African-Americans who have a higher risk for developing POAG. We conduct a multiethnic genome-wide association study (GWAS) of POAG in the GERA cohort, with replication in the UK Biobank (UKB), and vice versa, GWAS in UKB with replication in GERA. We identify 24 loci (P < 5.0 × 10−8), including 14 novel, of which 9 replicate (near FMNL2, PDE7B, TMTC2, IKZF2, CADM2, DGKG, ANKH, EXOC2, and LMX1B). Functional studies support intraocular pressure-related influences of FMNL2 and LMX1B, with certain Lmx1b mutations causing high IOP and glaucoma resembling POAG in mice. The newly identified loci increase the proportion of variance explained in each GERA race/ethnicity group, with the largest gain in African-Americans (0.5–3.1%). A meta-analysis combining GERA and UKB identifies 24 additional loci. Our study provides important insights into glaucoma pathogenesis.
Highlights
Primary open-angle glaucoma (POAG) is a leading cause of irreversible vision loss, yet much of the genetic risk remains unaccounted for, especially in African-Americans who have a higher risk for developing POAG
We investigated 9 novel glaucoma-associated loci from UK Biobank (UKB) in GERA, and 6 of the novel loci replicated at Bonferroni significance
Our results confirmed the association of variants with POAG in 14 previously reported loci, including TGFBR3, TMCO1, AFAP1, FOXC1, GMDS, CDKN1A, CAV1/CAV2, CDKN2B-AS1, ABCA1, ARHGEF12, ATXN2, SIX1/SIX6, GAS7, and TXNRD2
Summary
Primary open-angle glaucoma (POAG) is a leading cause of irreversible vision loss, yet much of the genetic risk remains unaccounted for, especially in African-Americans who have a higher risk for developing POAG. There is a lack of studies investigating genetic risk factors influencing POAG susceptibility in African ancestry populations and Hispanic/Latino individuals, with only one GWAS published to date[14]. This is a important gap in our understanding of glaucoma etiology, because of the higher prevalence of POAG in these populations (https://nei.nih.gov/health/glaucoma/glaucoma_ facts). The current study identifies a total of nine novel loci associated with the risk of POAG or glaucoma at genome-wide significance that replicated in an independent sample, and demonstrates relevant function of FMNL2 and LMX1B using cell line and mouse experiments
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