From phenotype to genotype: glaucoma and psychiatric disorders

Abstract

Purpose : To measure the phenotypic and genotypic associations between glaucoma and psychiatric disorders.

Methods : A total of 169, 362 participants from the UK Biobank cohort were included in the phenotypic analysis, participants underwent detailed questionnaire and standardized physical examinations between 2006 and 2010 and were followed up until 2021. Multivariable Cox regression models were used to investigate the relationship between glaucoma and incident psychiatric disorders. A total of 674,296 samples of glaucoma cohorts and 449,203 samples of psychiatric disorders cohorts from previous genome-wide association studies were included in the genotypic analysis. The conditional/conjunctional false discovery rate methodology was utilized to estimate the specific overlapping loci between glaucoma and psychiatric disorders. Gene expression analysis in the human brain and aqueous humor outflow pathways was further offered to provide independent experimental evidence. The associations of the identified overlapping loci with phenotypes were further validated among the UK biobank participants.

Results : A total of 5,527 participants had glaucoma at baseline. The multivariable-adjusted hazard ratio (HR) (95%confidence interval [CI]) for glaucoma associated with total four psychiatric disorders was 1.11 (1.03-1.21). Specifically, the presence of glaucoma was significantly associated with increased risk of an incident anxiety disorder (HR, 1.33; 95% CI 1.09-1.62). We identified ten independent genomic variants shared between glaucoma and anxiety disorder and between glaucoma and major depressive disorder, encompassing variants predicted to regulate genes expressed in human aqueous humor outflow pathways and the brain. The independent genomic variants rs7310615, rs9820228, rs9831374, rs7784849, rs2193255, rs72963135, and rs11030381 were validated to correlate with both glaucoma and the traits of psychiatric disorders in the UK biobank.

Conclusions : We found that glaucoma was associated with an increased risk of developing anxiety disorder in the UK longitudinal database. Consistently, we found genetic evidence supporting the shared biological basis of comorbidity between glaucoma and psychiatric disorders. This study adds to the body of literature implicating shared genetic architecture as a potential etiology for relationships between glaucoma and psychiatric disorders, and provides insight on their pathogenesis and novel therapeutic targets.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.