Genetic Association and Linkage at Putative Risk Loci for Primary Open-angle Glaucoma

Abstract

Purpose : More than a dozen genetic risk loci for the common, late-onset form of glaucoma have been identified, but the majority of the genetic risk is still unknown. Here, we report a survey of genetic association and linkage for primary open-angle glaucoma (POAG) within and near 14 loci in previously reported POAG risk loci to better characterize these genomic regions and to identify novel genetic determinants.

Methods : The NEIGHBORHOOD Consortium has genotyped 6,044 unrelated primary open-angle glaucoma (POAG) cases (n = 3,208) and controls (n = 2,836) of European descent for more than 240,000 mainly protein-coding genetic variants on the Illumina HumanExome BeadChip, with additional content of 15,800 variants in genomic regions implicated in glaucoma. We conducted association analysis for single variants by logistic regression, adjusting for age at recruitment, sex, DNA source and three principal components for ancestry, as well as gene-based tests using SKAT-O including all variation with minor allele frequency less than 0.1 or 0.02, using the default weighting scheme. We performed linkage analysis using a set of 84 families (155 POAG cases, 104 controls) containing an index case with severe POAG, using dominant inheritance model with reduced penetrance and a sporadic (non-genetic or phenocopy) rate of 0.03.

Results : Association at studywide significance (nominal p < 0.00017) was detected for one or more common variants in AFAP1, ATXN2, CAV1, CDKN2B-AS1, SIX6 and TMCO1, including missense variants in ATXN2 (W262R) and SIX6 (H141N). Genes FNDC3B and AFAP1 contained multiple rare coding variants enriched in either cases (OR > 2) or controls (OR < 0.5), and thus had suggestive SKAT-O results (p = 0.005 and 0.008 respectively). Two-point LOD scores greater than 1.5 were also observed in or near MYOC, ABCA1, GAS7 and TXNRD2.

Conclusions : We have confirmed genetic association and have detected suggestive evidence of linkage at several loci previously implicated in POAG. These findings improve our understanding of the genetic basis of this common eye disease, and suggest that some causal variation remains to be uncovered.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.