Genome-wide association study for primary angle closure glaucoma in Europeans identifies novel loci related to iris colour and morphology

Abstract

Purpose : Primary angle closure glaucoma (PACG) is an important cause of preventable blindness. Previous genome-wide association studies (GWAS) have largely derived from Asian populations and it remains unclear whether the genetic causes of PACG differ in Europeans. We carried out the first large-scale discovery GWAS of PACG in Europeans, replicating our findings in 5 independent studies.

Methods : GWAS discovery used European participants of the UK Biobank (UKB) study. PACG status was ascertained using ICD 9/10 coding from linkage to hospital-based medical records in UKB and clinically in the replication cohorts from Europe, Australia and the Americas. All cohorts were genotyped using the UKB Axiom Array with variants imputed using the Haplotype Reference Consortium and other panels. Association was tested genome-wide with logistic regression and linear mixed models adjusting for age, sex and the first 10 genomic principal components (PCs), using the software REGENIE. Only participants of European ancestry, identified through clustering of PCs, were included in the study. Conditional and joint analysis of the UKB summary statistics using GCTA COJO identified independent genome-wide significant loci which were tested for association in replication cohorts.

Results : The study analysed 440 611 discovery and 8536 replication participants, of which 1783 and 694 respectively were PACG cases. Five genomic regions were associated with PACG at genome-wide significance (P<5x10^-8). The strongest replicated association was within the HERC2 gene (rs12913832:A , OR=1.29, P=2.1x10^-10), an allele that has been previously associated with brown iris colour. Another novel locus SEMA3A (P=2.4x10^-8) has reported associations with morphological characteristics and colour of the iris. We also found significant associations with PACG at the PXDNL (P=3.9x10^-15) and GLIS3 (P=3.4x10^-10) gene loci, both previously reported as associated with PACG in Asian populations, and at PCDH7 (P=5.2x10^-9).

Conclusions : Novel loci at HERC2 and SEMA3A, genes related to iris morphology and pigmentation, were associated with PACG in this large study of genetically European participants. The most plausible interpretation is that these loci affect PACG risk via changes in iris anatomy, and they may only be evident in European populations where eye colour is heterogeneous.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

 

Manhattan plot for PACG discovery