Abstract
Purpose :
There is disparity in POAG prevalence, clinical presentations and outcomes across ancestries. Our previous Global Biobank Meta-analysis Initiative (GBMI) POAG meta-analysis, the largest and most diverse to date, from ~1.48 million individuals from six ancestries identified a total of 109 GWAS loci, 18 of which were novel. Ten of the GWAS loci are ancestry-specific. Additionally, we show heterogeneity in effects for 14 loci across ancestries and sexes. Considering genetic interactions may contribute to phenotypic complexity, we hypothesize that ancestry specific genetic interaction in POAG underlie observed disparity. In GBMI analysis we found evidence of a significant interaction between multi-ancestry SIX6 rs33912345 and causal variants in CDKN2B-AS1 locus, with concomitant effect on expression of CDKN2A, and CDKN2B.
Methods :
We tested for genetic interactions in BioVU data for a subset of 65 lead SNPs that represent just over half of the overall loci identified in our GBMI study. We determined interaction using wtest in 49,034 European and 3573 African American BioVU patients. We further checked the effect of the loci i) that show interaction in both ancestries, and ii) with the highest number of significant pairwise interaction with other POAG loci in European patients, by checking the differences in the measured gene expressions of genes in a target locus in GTEx skeletal muscle tissues (N=716) between the haplotype background that has the reference and derived alleles. Statistical difference in expression was determined using ANOVA.
Results :
We identified a total of 187 and 126 pairwise interactions in European and African American patients, respectively (p<0.05). These interactions are mainly due to 18 core loci with ≥5 pairwise interactions with other loci across the two ancestries: 6 common to both ancestry and 6 unique to each ancestry. Four core loci unique to African BioVu patients are African-specific. Chr3_rs62250629_CADM2 locus has pairwise interactions with 27 and 9 other loci in European and African American patients, respectively. The lead variant in the locus has significant trans effect on NEAT1 (p= 0.006) gene in chr11_ rs12789028 locus and interact with local GTEx eQTL to alter its expression pattern.
Conclusions :
Our findings, if replicated (in other GBMI biobanks), point to genetic interactions as additional contributor to observed disparities in POAG.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.