Abstract
Purpose :
In genome-wide association studies(GWAS), X chromosome(ChrX) variants were not fully investigated. Sex-specific effects and ChrX-specific quality control(QC) are needed to examine these effects. Previous work identified 52 autosomal variants associated with age-related macular degeneration(AMD) via the International AMD Genomics Consortium(IAMDGC), but did not analyze ChrX. Therefore, we aim to investigate ChrX variants for AMD association.
Methods :
We genotyped 29,269 European individuals(M/F:10,404/18,865;AMD:12,087/14,273) via custom chip and imputed after ChrX-specific QC(XWAS 3.0) using the Michigan Imputation Server. Imputation generated 1,221,623 variants on ChrX. Another imputation included non-Europeans(total:52,189 individuals) via the TOPMed Imputation server, generating 5,869,633 ChrX variants. Age,informative PCs,and subphenotypes were covariates for logistic association analyses with Fishers correction. Gene/pathway analyses were performed with VEGAS,GSEASNP,ICSNPathway,DAVID,and mirPath.
Results :
Via logistic association on Europeans with sex correction, variants in/near the genes SLITRK4,ARHGAP6,FGF13 and DMD were nominally associated with AMD(P<1x10-6,Fishers combined-corrected). Via association testing of subphenotypes of choroidal neovascularization and geographic atrophy(GA), variants in DMD associated with GA(P<1x10-6,Fishers combined-corrected). Via gene-based analysis with VEGAS, several genes were AMD-associated(P<0.05, both truncated tail strength/truncated product P) including SLITRK4 and BHLHB9. Pathway analysis using GSEASNP and DAVID showed genes associated with nervous system development(FDR: P:0.02), and blood coagulation(FDR: P:0.03). Variants in the region of a microRNA(miR) were AMD-associated(P<0.05, truncated tail strength/truncated product P). Via DIANA mirPath analysis, downstream targets of miRs show association with brain disorders and fatty acid elongation(P<0.05). A long-non coding RNA on ChrX near the DMD locus was also AMD-associated(4x10-7). Epistatic analysis testing a t-statistic for a quantitative trait found an association that was different between cases/controls in the XG gene.
Conclusions :
ChrX variants may show an association with AMD pathogenesis, and these variants may be linked to novel pathways. Further analysis is needed to confirm results and to understand their biological significance and relationship with AMD development in worldwide populations.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.