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Abstract #116776 Published in IGR 24-4
Novel ancestry-specific primary open-angle glaucoma loci and shared biology with vascular mechanisms and cell proliferation
Lo Faro V; Bhattacharya A; Zhou W; Zhou D; Wang Y; Läll K; Kanai M; Lopera-Maya E; Straub P; Pawar P; Tao R; Zhong X; Namba S; ; Sanna S; Nolte IM; Okada Y; Ingold N; Macgregor S; Snieder H; Surakka I; Shortt J; Gignoux C; Rafaels N; Crooks K; Verma A; Verma SS; Guare L; Guare L; Rader DJ; Willer C; Martin AR; Brantley MA; Gamazon ER; Jansonius NM; Joos K; Cox NJ; Hirbo JCell reports. Medicine 2024; 5: 101430
Primary open-angle glaucoma (POAG), a leading cause of irreversible blindness globally, shows disparity in prevalence and manifestations across ancestries. We perform meta-analysis across 15 biobanks (of the Global Biobank Meta-analysis Initiative) (n = 1,487,441: cases = 26,848) and merge with previous multi-ancestry studies, with the combined dataset representing the largest and most diverse POAG study to date (n = 1,478,037: cases = 46,325) and identify 17 novel significant loci, 5 of which were ancestry specific. Gene-enrichment and transcriptome-wide association analyses implicate vascular and cancer genes, a fifth of which are primary ciliary related. We perform an extensive statistical analysis of SIX6 and CDKN2B-AS1 loci in human GTEx data and across large electronic health records showing interaction between SIX6 gene and causal variants in the chr9p21.3 locus, with expression effect on CDKN2A/B. Our results suggest that some POAG risk variants may be ancestry specific, sex specific, or both, and support the contribution of genes involved in programmed cell death in POAG pathogenesis.
Department of Ophthalmology, Amsterdam University Medical Center (AMC), Amsterdam, the Netherlands; Department of Clinical Genetics, Amsterdam University Medical Center (AMC), Amsterdam, the Netherlands; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
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