Phenome-wide association analysis on risk variants for age-related macular degeneration reveals shared genetic influences with a wide range of disorders: the Million Veteran Program

Abstract

Purpose : Age-related macular degeneration (AMD) is a leading cause of irreversible blindness with complex causes and a prominent heritable component. Here, we applied phenome-wide association analysis (PheWAS) to a large sample of US Veterans of European ancestry from the Million Veteran Program (MVP), scanning 907 common disorders for 50 AMD-associated risk loci that we recently identified by genome-wide association meta-analysis of MVP and several other AMD cohorts.

Methods : Our sample comprised 275,104 unrelated European American Veterans (≥ 30 years old at enrollment in the MVP), with ≥ 2 separate visits to the VA Healthcare System in each of the two years immediately prior to enrollment. Association analysis was performed with each marker using 907 PheCodes as outcomes, collections of ICD9 codes representing a given disease or phenotype, from 1,007 previously obtained PheCodes (Klarin et al., 2018, Nat Genet 50, 1514), with prevalence ≥ 0.25% in our sample. Analyses used the PheWAS package for the R statistical programming language (v3.2.0), with adjustment for age at enrollment, sex and five European-specific principal components of ancestry, assuming an additive inheritance model.

Results : A total of 222 marker/phenotype pairs, representing 104 unique phenotypes, were significantly associated (nominal p < 1.1 × 10^–6 after Bonferroni correction for 907 traits and 50 markers). Ocular traits related to retinal diseases were common (24 traits; 102 associations with 25 markers), as were cardiovascular disease (14 traits), diabetes and lipid metabolic diseases (22 traits), dementia-related disorders (12 traits) and neoplasms/cancers (11 traits). Marker rs429358 in APOE, had the largest number of significant associations (42 traits). Relaxing the significance to a suggestive level, p < 1 × 10^–4 yielded 361 associations over 160 unique traits.

Conclusions : PheWAS analysis revealed additional evidence for a genetic link between AMD and traits related to lipid metabolism and angiogenesis, which were previously implicated through physiological studies. Novel links between AMD and a wide range of other disorders were revealed through strongly associated genetic variants. Closer examination of the shared genetics may reveal new causal pathways for AMD.

This is a 2020 ARVO Annual Meeting abstract.