Statistical driver genes as a means to uncover missing heritability for age-related macular degeneration

BACKGROUND: Age-related macular degeneration (AMD) is a progressive retinal disease contributing to blindness worldwide. Multiple estimates for AMD heritability (h(2)) exist; however, a substantial proportion of h(2) is not attributable to known genomic loci. The International AMD Genomics Consortium (IAMDGC) gathered the largest dataset of advanced AMD (ADV) cases and controls available and identified 34 loci containing 52 independent risk variants defining known AMD h(2). To better define AMD heterogeneity, we used Pathway Analysis by Randomization Incorporating Structure (PARIS) on the IAMDGC data and identified 8 statistical driver genes (SDGs), including 2 novel SDGs not discovered by the IAMDGC. We chose to further investigate these pathway-based risk genes and determine their contribution to ADV h(2), as well as the differential ADV subtype h(2). METHODS: We performed genomic-relatedness-based restricted maximum-likelihood (GREML) analyses on ADV, geographic atrophy (GA), and choroidal neovascularization (CNV) subtypes to investigate the h(2) of genotyped variants on the full DNA array chip, 34 risk loci (n = 2758 common variants), 52 variants from the IAMDGC 2016 GWAS, and the 8 SDGs, specifically the novel 2 SDGs, PPARA and PLCG2. RESULTS: Via GREML, full chip h(2) was 44.05% for ADV, 46.37% for GA, and 62.03% for CNV. The lead 52 variants’ h(2) (ADV: 14.52%, GA: 8.02%, CNV: 13.62%) and 34 loci h(2) (ADV: 13.73%, GA: 8.81%, CNV: 12.89%) indicate that known variants contribute ~ 14% to ADV h(2). SDG variants account for a small percentage of ADV, GA, and CNV heritability, but estimates based on the combination of SDGs and the 34 known loci are similar to those calculated for known loci alone. We identified modest epistatic interactions among variants in the 2 SDGs and the 52 IAMDGC variants, including modest interactions between variants in PPARA and PLCG2. CONCLUSIONS: Pathway analyses, which leverage biological relationships among genes in a pathway, may be useful in identifying additional loci that contribute to the heritability of complex disorders in a non-additive manner. Heritability analyses of these loci, especially amongst disease subtypes, may provide clues to the importance of specific genes to the genetic architecture of AMD.