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

Abstract

Background: Genetic 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.

Methods: We 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 Alzheimer's disease risk hierarchy (ε2/ε2<ε2/ε3<ε3/ε3<ε2/ε4<ε3/ε4<ε4/ε4), 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).

Findings: In 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=1.8×10^-129), dementia, and Alzheimer's disease (OR 1.55 [1.40-1.70]; P=5×10^-19), and a reduced odds of fatty liver disease (OR 0.93 [0.90-0.95]; P=1.6×10^-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=1.1×10^-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.

Interpretation: We 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.

Figure 1.

APOE PheWAS results from the entire cohort and its accompanying QQ plot. APOE genotypes were arranged hierarchically from ε2 to ε4 (ε2/ε2<ε2/ε3<ε3/ε3<ε2/ε4<ε3/ε4<ε4/ε4). PheWAS analysis was adjusted for EHR length, age, sex, and PCs 1–16. In this cohort, 2,318 phecodes with more than 50 cases or controls were analyzed for association with APOE variants. The green horizontal line represents Bonferroni correction level (α=2.16×10⁻⁰⁵) and the red line represents the nominal significance (α=0.05). Furthermore, the direction of arrows indicates either an increased or decreased OR. The x-axis represents the tested phecodes and the broader 18 categories they belong to, and the y-axis shows the −log₁₀(P-value).

Figure 2.

Volcano plot of P-values on y-axis against their corresponding odds ratios on x-axis after the PheWAS of the whole cohort. The 17 top hits in this analysis are tagged and labeled in orange. The plot shows AD had the largest effect size while hyperlipidemia had the lowest P-value. Moreover, 14 associations are positively associated with APOE genotypes, whereas 3 phecodes are inversely associated. N.B. the y-axis is log transformed (log(−log₁₀ (P-value))) for better visualization with a cut-off at −2.

Figure 3.

Plot illustrates odds ratios from three separate analyses combined. The top hits from the PheWAS for the whole cohort were used to extract the similar phecodes from PheWAS summary outcomes in females and males. We can see that confidence intervals follow the similar patterns in three analyses and are larger in AD and dementias compared to other phecode categories. The results of heterogeneity test, I² and P-value, for each phecode is presented in the label of each corresponding phecode. One phecode, noninflammatory disorders of vulva and perineum, was excluded from the heterogeneity test because it was available for females. Four out of 16 tests indicated heterogeneity in results (P-values<0.05). These phecodes were hyperlipidemia, hypercholesterolemia, pure hypercholesterolemia, and mixed hyperlipidemia.

Figure 4.

The forest plot displays the combined odds ratios from six separate analyses across ancestral groups. The 17 top hits from the PheWAS for the whole cohort were used to extract the similar phecodes from PheWAS summary outcomes in ancestral groups. Not all the above phecodes had case counts above 50 in all ancestral categories, such as AD appearing only for EUR and AMR. The results of heterogeneity test, I² and P-value, for each phecode is presented in the label of the corresponding phecode. Three associations including hyperlipidemia, mild cognitive impairment, and symptoms and signs involving cognitive functions and awareness indicated heterogeneity in results (P-values<0.05).