Pleiotropic effects of APOE variants on a sleep-based adult epidemiological cohort

Phenome Wide Association study (PheWAS) approach was applied in a sleep-based adult epidemiological cohort to address pleiotropic effects of APOE variants in sleep patterns.

PheWAS analysis was performed on the São Paulo Epidemiologic Sleep Study (EPISONO), an adult epidemiological sample (1042 individuals) submitted to objective and subjective sleep evaluations, laboratory tests, clinical scales, anthropomorphic measurements and sociodemographic inquiries (1182 traits per individual). We determined APOE alleles using SNP-array and qPCR data. PheWAS was performed with an additive genetic model for the variant rs7412, using age, age², sex, principal components, socioeconomic classification and body mass index as covariates. Validation analysis was performed for combinations of APOE full haplotypes (ε3ε3, ε2ε2, ε4ε4, ε2ε3, ε2ε4, and ε3ε4).

When all covariates were applied, nominal associations (p < 0.05 in PheWAS) between the rs7412 genotype and 5 continuous traits were identified and confirmed by non-parametric tests: LDL and total cholesterol blood concentrations, Morningness-Eveningness Questionnaire (MEQ) score, power of gamma and beta electroencephalographic (EEG) frequency bands in N1 and N3, respectively. The association with LDL levels remained significant after Bonferroni correction. All these 5 traits were significantly associated at nominal level with at least 1 of the APOE haplotype combinations. Lower LDL and cholesterol levels were associated with ε2ε3 genotype, higher MEQ scores were observed in ε2ε2 individuals, higher power of gamma waves in N1 was associated with ε2ε2, ε2ε3 and ε4ε4 (with indication of putative dosage effect for ε2 haplotype), and higher power of beta waves in N3 was associated with the ε2ε3 genotype.

Extensive APOE associations with lipid metabolism were replicated in an admixed cohort, despite sample size limitations. Suggestive associations of APOE genotype with diurnal preference scores and variables derived from sleep EEG spectral analysis present preliminary evidence of the effect of these variants over sleep patterns and individual differences in circadian typology.