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

ABSTRACT: BACKGROUND:The three main alleles of the APOE gene (?4, ?3 and ?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 ?3?3 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, ?3?4 and ?4?4 genotypes associated with increased odds of AD (p ? 7.6 × 10-46), hypercholesterolaemia (p ? 7.1 × 10-17) and ischaemic heart disease (p ? 2.3 × 10-4), while ?2?3 provided protection for the latter two conditions (p ? 3.7 × 10-10) compared to ?3?3. In contrast, ?4-associated disease protection was seen against obesity, chronic airway obstruction, type 2 diabetes, gallbladder disease, and liver disease (all p ? 5.2 × 10-4) while ?2?2 homozygosity increased risks of peripheral vascular disease, thromboembolism, arterial aneurysm, peptic ulcer, cervical disorders, and hallux valgus (all p ? 6.1 × 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 ?4-associated disease protection and harmful effects of the ?2?2 genotype, for several conditions. FUNDING:National Health and Medical Research Council of Australia.

SUBMITTER: Lumsden AL 

PROVIDER: S-EPMC7452404 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature