Abstract
Purpose :
Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly. Genome-wide association studies (GWAS) have identified common and rare variants in genes in the complement pathway associated with AMD. To identify additional AMD risk variants and better understand the underlying disease mechanisms, we sequenced the genomic regions of genes in the alternative complement system, coagulation, and inflammatory pathways in 481 advanced AMD (AAMD) and 277 unaffected subjects.
Methods :
This study included 758 subjects, of which 340 subjects were from 76 families densely affected by AAMD. Targeted sequencing was performed on the genomic regions of 150 genes in 111 samples. Whole exome sequencing was performed on the other 647 samples. Single-variant tests were performed on 3062 variants shared among ≥ 5 AAMD subjects using logistic regression. Gene-based tests were used to evaluate aggregate effects from rare and low frequency variants (at minor allele frequency [MAF] <5%) in a gene using burden tests and SKAT. Analyses were adjusted for age, sex, smoking, four principal components, and family structure.
Results :
At false discovery rate (FDR) <0.05, we identified a protein-altering variant, rs2274700 in CFH (Odds ratio=0.61, P=1.78x10-5) in association with AMD by single-variant analysis. rs2274700 is a perfect proxy of a well-known AMD intronic SNP rs1410996 (linkage disequilibrium, r2=1). Gene-based tests identified a burden of 24 variants in OPRM1 (PSKAT=0.002) and 18 in LCT (PSKAT=0.003) at FDR<0.2. For densely AAMD affected families whose members had low genetic risk score (<0.8) and no known rare variants of AMD, we hypothesized that some of those families may be explained by variants that are highly penetrant. Among the 82 extremely rare variants with MAF <0.001 in the 1000 genomes reference panel and being predicted in silico to have functional impact on proteins, we identified one highly penetrant protein-altering variant, whose risk allele was found in ≥ 80% affected AMD members in a family, but not in any of the other samples.
Conclusions :
Our study suggested novel pathogenetic rare variants and genes in immune pathways for AMD. Further functional studies will be necessary to validate our findings that will guide the design for novel therapeutic strategies for the disease.
This is a 2021 ARVO Annual Meeting abstract.