Polygenic risk score identifies associations between sleep duration and diseases determined from an electronic medical record biobank

Abstract

Study Objectives

We aimed to detect cross-sectional phenotype and polygenic risk score (PRS) associations between sleep duration and prevalent diseases using the Partners Biobank, a hospital-based cohort study linking electronic medical records (EMR) with genetic information.

Methods

Disease prevalence was determined from EMR, and sleep duration was self-reported. A PRS for sleep duration was derived using 78 previously associated SNPs from genome-wide association studies (GWAS) for self-reported sleep duration. We tested for associations between (1) self-reported sleep duration and 22 prevalent diseases (n = 30 251), (2) the PRS and self-reported sleep duration (n = 6903), and (3) the PRS and the 22 prevalent diseases (n = 16 033). For observed PRS-disease associations, we tested causality using two-sample Mendelian randomization (MR).

Results

In the age-, sex-, and race-adjusted model, U-shaped associations were observed for sleep duration and asthma, depression, hypertension, insomnia, obesity, obstructive sleep apnea, and type 2 diabetes, where both short and long sleepers had higher odds for these diseases than normal sleepers (p < 2.27 × 10⁻³). Next, we confirmed associations between the PRS and longer sleep duration (0.65 ± 0.19 SD minutes per effect allele; p = 7.32 × 10⁻⁰⁴). The PRS collectively explained 1.4% of the phenotypic variance in sleep duration. After adjusting for age, sex, genotyping array, and principal components of ancestry, we observed that the PRS was also associated with congestive heart failure (CHF; p = 0.015), obesity (p = 0.019), hypertension (p = 0.039), restless legs syndrome (RLS; p = 0.041), and insomnia (p = 0.049). Associations were maintained following additional adjustment for obesity status, except for hypertension and insomnia. For all diseases, except RLS, carrying a higher genetic burden of the 78 sleep duration-increasing alleles (i.e. higher sleep duration PRS) associated with lower odds for prevalent disease. In MR, we estimated causal associations between genetically defined longer sleep duration with decreased risk of CHF (inverse variance weighted [IVW] OR per minute of sleep [95% CI] = 0.978 [0.961–0.996]; p = 0.019) and hypertension (IVW OR [95% CI] = 0.993 [0.986–1.000]; p = 0.049), and increased risk of RLS (IVW OR [95% CI] = 1.018 [1.000–1.036]; p = 0.045).

Conclusions

By validating the PRS for sleep duration and identifying cross-phenotype associations, we lay the groundwork for future investigations on the intersection between sleep, genetics, clinical measures, and diseases using large EMR datasets.