Genome-wide association study identifies susceptibility loci for open angle glaucoma at TMCO1 and CDKN2B-AS1

Abstract

A genome-wide association study (GWAS) for open angle glaucoma (OAG) blindness was conducted using a discovery cohort of 590 cases with severe visual field loss and 3956 controls. Genome-wide significant associations were identified at TMCO1 (rs4656461 (G) OR=1.68, p=6.1x10 -10 ) and CDKN2B-AS1 (rs4977756 (A) OR = 1.50, p=4.7x10 -9 ). These findings were replicated in a second cohort of advanced OAG cases (rs4656461 p=0.010; rs4977756 p=0.042) and two further cohorts of less severe OAG. The study wide odds ratios are 1.51 (1.35-1.68), p=6.00x10 -14 at TMCO1, and 1.39 (1.28-1.51), p=1.35x10 -14 at CDKN2B-AS1 (also known as CDKN2BAS and ANRIL). Carriers of 1 or more risk alleles at both loci concurrently are at >3-fold increased risk of glaucoma. We demonstrate retinal expression of genes at both loci, and show that CDKN2A and CDKN2B are strongly upregulated in an animal model of glaucoma.Glaucoma is a group of neurodegenerative ocular diseases united by a clinically characteristic optic neuropathy. It is the second leading cause of blindness worldwide 1 . Primary open angle glaucoma (OAG) is the commonest subtype 1 . OAG pathogenesis and factors determining disease progression are poorly understood. Early intervention with measures to reduce intraocular pressure retards visual loss in most individuals 2 , but many cases of glaucoma remain undiagnosed until irreversible vision loss has occurred. Elucidation of SNPs associated with severe outcomes could enable better targeting of treatments which carry cost and morbidity, to individuals at highest risk of blindness. Linkage and candidate gene studies have identified several genes likely to be involved in OAG including myocilin 3 and NTF4 4 , although for the latter, findings have varied in different populations 5 . A recent GWAS using Icelandic OAG cases of unselected severity identified association with variants near CAV1 6 . To identify genes predisposing individuals to OAG blindness, we performed a GWAS in Australian Caucasians with advanced OAG (individuals with OAG who have progressed to severe visual field loss or blindness).

Current concepts on primary open-angle glaucoma genetics: a contribution to disease pathophysiology and future treatment

“…A role for both TMCO1 and CDKN2B-AS1 in the retinal ganglion cell apoptosis was proposed. 126 The most recently published study regarding identification of new loci associated with POAG is the one by Porter et al 127 who identified a new POAG locus, GLC1Q, on chromosome 4 at 4q35.1-q35.2. They investigated the genetic cause of POAG in a large four-generation family with an apparent autosomal dominant mode of inheritance using genome-wide linkage analysis, but they failed to identify a mutation within the critical region in the candidate genes LRPB2BP, CYP4V2 and UFSP2.…”

Expansive marker analysis replicating the association of glaucoma susceptibility with human chromosome loci 1q43 and 10p12.31

“…Recently, several POAG susceptibility loci were identified by genome-wide association (GWA) studies [16][17][18][19][20] and were replicated in multiple ethnicities: 7q31.2 between CAV1 and CAV2, 16,21 9p21.3 with CDKN2B-AS1, 19,20,[22][23][24][25][26] 10q21.3 with ATOH7, 17,18,22,27 and 14q23.1 between SIX1 and SIX6. 17,20,22,28 One of the GWA studies demonstrated the association of POAG with six SNPs that flanked the ZP4, PLXDC2, and TMTC2 genes located at chromosome loci 1q43, 10p12.31, and 12q21.31, respectively, in a Japanese population; 29 however, these associations were not replicated in a South Indian, 30 Afro-Caribbean, 24 or Chinese 31 population.…”

Genome-wide association studies: applications and insights gained in Ophthalmology

“…113 TMCO1, as mentioned previously, has been suggested to be associated with POAG. 31 Van Koolwijk et al 112 also investigated the effect of the minor alleles of these genes on POAG. The minor allele of GAS7, which decreased IOP by 0.19 mm Hg, reduced the glaucoma risk (OR ¼ 0.88, 95% CI ¼ 0.78-0.98).…”