Abstract
Purpose :
Primary open-angle glaucoma (POAG) is a heterogeneous disease with a broad range of trait expressions. Identifying endophenotype-associated variants can help classify disease subgroups and improve predictive models. Such studies remain limited in individuals of African ancestry, particularly in cohorts with well-characterized phenotypes. This study examined the genetic colocalization of SNPs from a POAG GWAS in individuals of African ancestry with key endophenotypes.
Methods :
We conducted a joint GWAS in three African ancestry datasets (n=11,275), including the Genetics of Glaucoma in People of African Descent (GGLAD) consortium, African Descent and Glaucoma Evaluation Study (ADAGES), and Primary Open-Angle African American Glaucoma Genetics (POAAGG) study. At each significant locus, we performed genetic colocalization analyses between results from the GWAS of case-control status and four quantitative traits from the POAAGG cohort, including intraocular pressure (IOP), cup-to-disc ratio (CDR), mean deviation (MD), and retinal nerve fiber layer (RNFL) thickness. We then performed locus quantification to visualize the change in CDR baseline measurements with respect to the genotypes. Lastly, we performed Mendelian randomization (MR) analysis at this locus.
Results :
We identified the locus for variant rs11824032 (chr11: 120354080) which maps to the ARHGEF12 gene; this region includes 2091 variants, all of which colocalized with a posterior probability (PP4 >0.8) between POAG and CDR baseline, satisfying the tested hypothesis that both traits are associated and share a single causal variant. Follow-up MR analyses for this variant with CDR baseline were also significant at p-value = 0.00082 (Beta = 0.083, SE = 0.02).
Conclusions :
We identified a novel locus that maps to the ARHGEF12 gene; this gene has previously been associated with elevated IOP in individuals of European ancestry. The genetic colocalization between this SNP and CDR baseline is a novel finding, and the significant MR p-value further corroborates the causality of this result. These findings suggest that the ARHGEF12 gene may influence POAG risk through CDR-mediated response mechanisms, suggesting a different disease mechanism in individuals of African ancestry.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.