Genome-wide association meta-analysis identifies novel ancestry-specific primary open-angle glaucoma loci and shared biology with vascular mechanisms and cell proliferation

Valeria Lo Faro; Arjun Bhattacharya; Wei Zhou; Dan Zhou; Ying Wang; Kristi Läll; Masahiro Kanai; Esteban A. Lopera-Maya; Péter Straub; Priyanka Prabhakar Pawar; Ran Tao; Xue Yun Zhong; Shinichi Namba; Serena Sanna; Ilja Maria Nolte; Yukinori Okada; Nathan Ingold; Stuart MacGregor; Harold Snieder; Ida L. Surakka; Jonathan Shortt; Christopher R. Gignoux; Nicholas M. Rafaels; Kristy Crooks; Anurag Verma; Shefali S. Verma; Lindsay A. Guare; Daniel James Rader; Cristen J. Willer; Alicia R. Martin

doi:10.1016/j.xcrm.2024.101430

Genetic & Genomic MedicineCell Reports MedicineFeb 1, 2024

Peer-reviewed journal article

Genome-wide association meta-analysis identifies novel ancestry-specific primary open-angle glaucoma loci and shared biology with vascular mechanisms and cell proliferation

Valeria Lo Faro iD, Arjun Bhattacharya iD, Wei Zhou iD, Dan Zhou iD, Ying Wang iD, Kristi Läll iD, Masahiro Kanai iD, Esteban A. Lopera-Maya iD, Péter Straub iD, Priyanka Prabhakar Pawar iD, Ran Tao iD, Xue Yun Zhong iD, Shinichi Namba iD, Serena Sanna iD, Ilja Maria Nolte iD, Yukinori Okada iD, Nathan Ingold iD, Stuart MacGregor iD, Harold Snieder iD, Ida L. Surakka iD, Jonathan Shortt iD, Christopher R. Gignoux iD, Nicholas M. Rafaels iD, Kristy Crooks iD, Anurag Verma iD, , Jibril B Hirbo iD

Abstract

Primary open-angle glaucoma (POAG) is a leading cause of irreversible blindness globally. There is disparity in POAG prevalence and manifestations across ancestries. We identify novel and unique genetics that underlie POAG risk in different ancestries by performing meta-analysis across 15 biobanks (of the Global Biobank Meta-analysis Initiative) with previously multi-ancestry studies. 18 novel significant loci, three of which were ancestry-specific, and five sex-specific were identified. We performed gene-enrichment and transcriptome-wide association studies (TWAS), implicating vascular and cancer genes. A fifth of these genes are primary ciliary genes. Extensive statistical analysis of genes in the SIX6 and CDKN2B-AS1 loci (implicated in POAG, cardiovascular diseases and cancers) found interaction between SIX6 and causal variants in chr9p21.3, with expression effect on CDKN2A/B. We infer that some POAG risk variants may be ancestry-specific, sex-specific, or both. Our results further support the contribution of vascular, cancer, and primary cilia genes in POAG pathogenesis.

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