Apolipoprotein E (APOE) genotype-associated disease risks: a phenome-wide, registry-based, case-control study utilising the UK Biobank

Background: The three main alleles of the APOE gene (epsilon 4, epsilon 3 and epsilon 2) carry differential risks for conditions including Alzheimer's disease (AD) and cardiovascular disease. Due to their clinical significance, we explored disease associations of the APOE genotypes using a hypothesis-free, data-driven, phenome-wide association study (PheWAS) approach. Methods: We used data from the UK Biobank to screen for associations between APOE genotypes and over 950 disease outcomes using genotype 8383 as a reference. Data was restricted to 337,484 white British participants (aged 37-73 years). Findings: After correction for multiple testing, PheWAS analyses identified associations with 37 outcomes, representing 18 distinct diseases. As expected, epsilon 3 epsilon 4 and epsilon 4 epsilon 4 genotypes associated with increased odds of AD (p <= 7.6 x 10(-46)), hypercholesterolaemia (p <= 7.1 x 10(-17)) and ischaemic heart disease (p <= 2.3 x 10(-4)), while 8283 provided protection for the latter two conditions (p <= 3.7 x 10(-10)) compared to 8383. In contrast, 84-associated disease protection was seen against obesity, chronic airway obstruction, type 2 diabetes, gallbladder disease, and liver disease (all p <= 5.2 x 10(-4)) while 8282 homozygosity increased risks of peripheral vascular disease, thromboembolism, arterial aneurysm, peptic ulcer, cervical disorders, and hallux valgus (all p <= 6.1 x 10(-4)). Sensitivity analyses using brain neuroimaging, blood biochemistry, anthropometric, and spirometric biomarkers supported the PheWAS findings on APOE associations with respective disease outcomes. Interpretation: PheWAS confirms strong associations between APOE and AD, hypercholesterolaemia, and ischaemic heart disease, and suggests potential epsilon 4-associated disease protection and harmful effects of the epsilon 2 epsilon 2 genotype, for several conditions. (C) 2020 The Authors. Published by Elsevier B.V.