STUDY OBJECTIVES
Since genome-wide association studies (GWAS) of sleep phenotypes have been conducted in differing populations and definitions of sleep phenotypes vary across studies, we investigated associations between several polygenic risk scores (PRSs) and potential sleep definitions among multiethnic cohorts.
METHODS
Using data from four cohorts (HCHS/SOL, ARIC, MESA, BHS, N = 16 895), we considered multiple definitions of short and long sleep, insomnia, and excessive daytime sleepiness (EDS). PRSs were developed based on summary statistics from GWAS in European ancestry individuals from the UK Biobank (UKB) and from GWAS conducted in a multiethnic population from the Million Veteran Program (MVP). Study-specific analyses estimated associations between sleep PRSs and corresponding sleep measures per 1 standard deviation increase in the PRS. Models were adjusted for age, sex, ancestral principal components, and center and race as appropriate. Results were meta-analyzed across studies.
RESULTS
PRSs based on European ancestry UKB GWAS had statistically significant associations with multiple definitions of the corresponding sleep phenotypes. Associations that were most consistent across studies included: short sleep PRS with ≤6 hours (OR = 1.23,p = 1.80x10-7,phet = 0.97); long sleep PRS with ≥9 hours (OR = 1.09,p = 6.76x10-4,phet = 0.77); insomnia PRS with the Women's Health Initiative Insomnia Rating Scale (WHIIRS) ≥10 or a subset of three questions ≥6 in ARIC (OR = 1.17,p = 5.51x10-10,phet = 0.69); and EDS PRS with Epworth Sleepiness Scale (ESS) ≥11 (OR = 1.23,p = 1.83x10-13,phet = 0.83). PRSs based on multi-ancestry MVP GWAS had weaker associations compared to those based on European ancestry only.
CONCLUSIONS
By evaluating several types of sleep PRSs and sleep phenotypes, we were able to highlight which sleep PRS performed well across diverse populations and which sleep definitions better captured genetic underpinnings.
A. Wyss, Michael Brown, Xiang Li et al.· Sleep· 0 citations
Background: Psychosocial stress is a key risk factor for coronary heart disease (CHD), particularly in postmenopausal women who face both a high stress burden and elevated cardiovascular risk. DNA methylation (DNAm), a critical epigenetic modification bridging environment and health, remains understudied as a contributor to stress-related CHD. Methods: We conducted an epigenome-wide association study (EWAS) of stress in the Women's Health Initiative (WHI), an ancestrally diverse cohort of postmenopausal women (n=3,857). At screening visit, participants completed a questionnaire assessing stressful life events and provided whole blood for DNAm. Incident CHD was then longitudinally ascertained (follow-up mean/SD: 16.7/8.4 years), and DNAm signatures were evaluated as CHD predictors using Cox regression. Predictive models were independently validated in the Jackson Heart Study (JHS; n=3,053) and Multi-Ethnic Study of Atherosclerosis (MESA; n=870). The bulk-level DNAm associations were computationally deconvolved at the cell-type-specific level using tensor composition analysis (TCA). Results: The EWAS in WHI identified 841 stress-related DNAm sites (99 hypermethylated, 742 hypomethylated with stress) after FDR correction, with 13 significant after Bonferroni correction, including sites located on immune and CHD-related genes (e.g., TNF, ALDH2). Methylation risk scores (MRSs) integrating the 841 FDR-significant sites (MRS841) and 13 Bonferroni-significant sites (MRS13) predicted incident CHD (HR=1.33-1.37; p[≤]0.0008) and mediated 16.5-17.7% of the association between stress and CHD. In JHS and MESA, MRS13 independently predicted CHD (HR=1.34; p=0.036), whereas MRS841 was suggestively associated with CHD (HR=1.27; p=0.087). TCA indicated that the greatest number of stress-related sites predictive of CHD was specifically in monocytes (133 total), with directions consistent with bulk-level associations (9 hypermethylated, 124 hypomethylated with stress). Conclusion: Our study supports methylation risk scores as novel biomarkers of stress-related CHD and uncovers epigenetic regulation in monocytes as a potential underlying mechanism. These findings highlight biological pathways linking stress and disease and may promote personalized interventions in high-risk populations.
Sofia Benavides, Hazel Milla, Helena Palma-Gudiel et al.· medRxiv· 0 citations