A multiethnic genome-wide association study of primary open-angle glaucoma identifies novel risk loci

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.

Role of matrix metalloproteinase‐9 gene polymorphisms in glaucoma: A hospital‐based study in Chinese patients

“…Reports have shown that incidence rate of glaucoma is higher in siblings compared with unrelated controls, indicating an important role of host genetics in predisposition to glaucoma. Recent genome wide association studies reveled role of ATP‐binding cassette transporter A1, actin filament‐associated protein 1, GDP‐mannose 4,6 dehydratase, phosphomannomutase 2, transforming growth factor beta receptor III, fibronectin type III domain containing 3B, rho guanine nucleotide exchange factor 12, growth arrest‐specific protein 7, forkhead box C1, ataxin‐2, thioredoxin reductase 2 with POAG, and PACG showed to be linked to ependymin related 1, choline acetyltransferase, gli‐similar protein 3, fermitin family member 2, and dolichyl‐phosphate mannosyltransferase subunit 2 . Furthermore, various candidate gene association studies presented association of single nucleotide polymorphisms with predisposition to development of POAG or PACG.…”

“…Recent genome wide association studies reveled role of ATP-binding cassette transporter A1, actin filament-associated protein 1, GDP-mannose 4,6 dehydratase, phosphomannomutase 2, transforming growth factor beta receptor III, fibronectin type III domain containing 3B, rho guanine nucleotide exchange factor 12, growth arrest-specific protein 7, forkhead box C1, ataxin-2, thioredoxin reductase 2 with POAG, and PACG showed to be linked to ependymin related 1, choline acetyltransferase, gli-similar protein 3, fermitin family member 2, and dolichyl-phosphate mannosyltransferase subunit 2. [6][7][8][9][10] Furthermore, various candidate gene association studies presented association of single nucleotide polymorphisms with predisposition to development of POAG or PACG. Role of matrix metalloproteinase-9 (MMP-9) variants have been well investigated in different populations as MMP-9 gene is responsible for remodeling of extracellular matrix.…”

A large cross-ancestry meta-analysis of genome-wide association studies identifies 69 novel risk loci for primary open-angle glaucoma and includes a genetic link with Alzheimer’s disease

“…POAG is highly heritable 4,5 , and previous genome-wide association studies (GWAS) have identified important loci associated with POAG risk and IOP [6][7][8][9][10][11][12][13][14] . Despite this success, the POAG genetic landscape remains incomplete and identification of novel risk loci is required to further define contributing disease mechanisms that could be targets of novel preventative therapies.…”

Genome wide-association study identifies novel loci in the Primary Open-Angle African American Glaucoma Genetics (POAAGG) study

“…A multi-ethnic genome-wide association study (GWAS) of the Genetic Epidemiology Research in Adult Health and Aging (GERA) cohort, which included individuals of African, Asian, Hispanic, and European descent, identified three novel and replicated variants near the PDE7B, TMCTC2, and FMNL2 genes. 39 A GWAS of South African and African American populations identified a novel candidate locus on the EXOC4 gene, but it did not associate in a West African replication cohort. 37 The African Descent and Glaucoma Evaluation Study (ADAGES) identified a novel association with advanced POAG and the EN04 locus.…”