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

Amanda L Lumsden; Anwar Mulugeta; Ang Zhou; Elina Hyppönen

doi:10.1016/j.ebiom.2020.102954

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

EBioMedicine. 2020 Sep:59:102954. doi: 10.1016/j.ebiom.2020.102954. Epub 2020 Aug 17.

Authors

Amanda L Lumsden¹, Anwar Mulugeta², Ang Zhou¹, Elina Hyppönen³

Affiliations

¹ Australian Centre for Precision Health, Cancer Research Institute, University of South Australia, Adelaide, SA 5001, Australia; South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia.
² Australian Centre for Precision Health, Cancer Research Institute, University of South Australia, Adelaide, SA 5001, Australia; South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia; Department of Pharmacology and Clinical Pharmacy, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia.
³ Australian Centre for Precision Health, Cancer Research Institute, University of South Australia, Adelaide, SA 5001, Australia; South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia. Electronic address: elina.hypponen@unisa.edu.au.

Abstract

Background: The three main alleles of the APOE gene (ε4, ε3 and ε2) 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 ε3ε3 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, ε3ε4 and ε4ε4 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 ε2ε3 provided protection for the latter two conditions (p ≤ 3.7 × 10^-10) compared to ε3ε3. In contrast, ε4-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 ε2ε2 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 ε4-associated disease protection and harmful effects of the ε2ε2 genotype, for several conditions.

Funding: National Health and Medical Research Council of Australia.

Keywords: APOE; Apolipoprotein E; Biomarkers; Disease risk; PheWAS; Phenome-wide association.

Publication types

Meta-Analysis

MeSH terms

Adult
Aged
Alleles
Apolipoproteins E / genetics*
Biological Specimen Banks
Case-Control Studies
Female
Genetic Association Studies*
Genetic Predisposition to Disease*
Genotype*
Humans
Male
Middle Aged
Phenotype
Population Surveillance
Registries
Risk Assessment
Risk Factors
United Kingdom / epidemiology

Substances

Apolipoproteins E