Diverse Ancestry Analysis: The IAMDGC 2.0

Abstract

Purpose : The previous genome-wide association (GWAS) analysis from the International Age-related Macular Degeneration Genomics Consortium (IAMDGC) based on 1000G-imputed data focused on 33,976 unrelated European (EUR) individuals and identified 52 independent variants from 34 loci for late AMD. Higher genetic coverage from TOPMed-imputed data and inclusion of individuals from other ancestries provide opportunities for an update of this analysis.

Methods : We here present a revisited analysis of IAMDGC data (IAMDGC 2.0) imputed to TOPMed-reference data (v2 imputation panel, build 38). Ancestry of each individual was determined by clustering its first two principal components with those from reference individuals from the Human Genome Diversity Project to define Asian (ASN), African (AFR), European (EUR), and unspecified other ancestry (OTH). By this, we identified 15,616/16,723 EUR, 207/322 ASN, 50/357 AFR, and 235/636 OTH cases of late AMD and AMD-free controls, respectively. We conducted ancestry-specific GWAS analyses of related and unrelated individuals adjusted for the first two PCs using a Firth test implemented in regenie and meta-analyzed the GWAS results with METAL. The total number of genetic variants analyzed (MAF>0.1, INFO>0.8) was 51,162,741 across ancestries.

Results : Among the 34 lead variants, we found a significant association for the HTRA1/ARMS2 locus (P<0.05/34=0.0015) for AFR, ASN, and EUR (OR=2.03, 95%CI=1.34-3.08; OR=2.23, 95%CI=1.68-2.95; OR=2.93, 95%CI=2.82-3.04 respectively). We did not find a significant association for CFH in the AFR population OR=0.81, 95%CI=0.53-1.26) but did in the ASN population(OR=0.57, 95%CI=0.42-0.76), and in the EUR(OR=0.38, 95%CI=0.36-0.39). Among the 34 lead SNPs, allele frequencies varied significantly in AFR or ASN compared to EUR (P<0.05/34=0.0015; 20/34 loci in ASN, 25/34 loci in AFR, Z-score 2 population testing). The cross ancestry meta-analysis did not yield any further genomic significant loci besides for the original 34 loci. In the meta-analysis, CFH and HTRA1/ARMS2 were in the same direction across ancestries, with a heterogeneity P-value of 0.001 and 0.01 respectively.

Conclusions : It is important to extend GWAS for advanced AMD to diverse ancestries. Our results support the ARMS1/HTRA2 locus as the strongest genetic locus for AMD in diverse ancestries with comparable ORs. Our results also document differential frequencies amongst different ancestries with AMD.

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