Phenome-Wide Association of APOE Alleles in the All of Us Research Program

BackgroundGenetic variation in APOE is associated with altered lipid metabolism, as well as cardiovascular and neurodegenerative disease risk. However, prior studies are largely limited to European ancestry populations and differential risk by sex and ancestry has not been widely evaluated. We utilized a phenome-wide association study (PheWAS) approach to explore APOE- associated phenotypes in the All of Us Research Program. MethodsWe determined APOE alleles for 181,880 All of Us participants with whole genome sequencing and electronic health record (EHR) data, representing seven gnomAD ancestry groups. We tested association of APOE variants, ordered based on Alzheimers disease risk hierarchy ({varepsilon}2/{varepsilon}2<{varepsilon}2/{varepsilon}3<{varepsilon}3/{varepsilon}3<{varepsilon}2/{varepsilon}4<{varepsilon}3/{varepsilon}4<{varepsilon}4/{varepsilon}4), with 2,318 EHR-derived phenotypes. Bonferroni-adjusted analyses were performed overall, by ancestry, by sex, and with adjustment for social determinants of health (SDOH). FindingsIn the overall cohort, PheWAS identified 17 significant associations, including an increased odds of hyperlipidemia (OR 1.15 [1.14-1.16] per APOE genotype group; P=1.8x10-129), dementia, and Alzheimers disease (OR 1.55 [1.40-1.70]; P=5x10-19), and a reduced odds of fatty liver disease (OR 0.93 [0.90-0.95]; P=1.6x10-9) and chronic liver disease. ORs were similar after SDOH adjustment and by sex, except for an increased number of cardiovascular associations in males, and decreased odds of noninflammatory disorders of vulva and perineum in females (OR 0.89 [0.84-0.94]; P=1.1x10-5). Significant heterogeneity was observed for hyperlipidemia and mild cognitive impairment across ancestry. Unique associations by ancestry included transient retinal arterial occlusion in the European ancestry group, and first-degree atrioventricular block in the American Admixed/Latino ancestry group. InterpretationWe replicate extensive phenotypic associations with APOE alleles in a large, diverse cohort, despite limitations in accuracy for EHR-derived phenotypes. We provide a comprehensive catalog of APOE-associated phenotypes and present evidence of unique phenotypic associations by sex and ancestry, as well as heterogeneity in effect size across ancestry. FundingFunding is listed in the acknowledgements.