Genomic Landscape of Rare and Common Variants in a Longitudinal Cohort Indicates Modifiers of Disease Pathogenesis

Abstract

Purpose : To understand the genomic landscape of rare and common glaucoma and anterior segment dysgenesis (ASD)-associated variants in the longitudinal Andhra Pradesh Eye Disease Study (APEDS) cohort for identifying their appropriateness as “controls” and as potential modifiers of disease pathogenesis.

Methods : The APEDS is a population-based rural cohort that was enrolled (1996-2000) from the State of Andhra Pradesh in Southern India and followed up at 10 and 15 years. The final follow up included 5395 subjects who underwent comprehensive clinical examination, deep phenotyping and assessments of risk factors. They were screened using a targeted panel comprising genes involved in glaucoma and ASD along with their interacting partners by deep sequencing. The data was analysed by GATK and VarSeq softwares and included subjects who had no visual impairments from baseline until the last follow up (n=2500). The APEDS cohort was assessed in conjunction with data on five ethnic populations of Indian origin (EPIO) represented in the gnomAD database (n=489) and compared to the overall mutation spectrum across all forms of primary glaucoma and ASD. The observed multi-allelic interactions in a subject were functionally assessed.

Results : The share of rare pathogenic alleles reported across the 25 glaucoma associated genes (n=221) were significantly higher (p<0.01; OR=3.01; 95%CI, 1.82-4.91) in the APEDS cohort (n=65; 29.45%) compared to EPIO (n=27; 12.21%) that contributed to a population attributable risk percent (PAR%) of 26.08. Similarly, among the ASD-associated pathogenic alleles (n=66) across 15 genes, the number of shared alleles were significantly higher (p<0.05; OR=2.57, 95%CI, 1.15-5.73) in the APEDS cohort compared to EPIO with a PAR% of 22.92. The common variants did not exhibit much variability across these datasets. Co-inheritance of multiple alleles contributed to 10.08% of all pathogenic variations and subsets of these indicated perturbation of their physical interactions, which could act as potential modifiers.

Conclusions : The overall landscape of gene variants in the APEDS cohort suggested that genetic assessments should be based on geographical and local ethnicity towards assessing the role of pathogenic alleles and potential modifiers in glaucoma and ASD cases. The limited variability across EPIO dataset limits their use as random “controls” in the Indian context.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.