Gene-environment interactions contribute to blood pressure variation across global populations

ABSTRACT Understanding the interplay between genetic architecture and environmental exposures is essential for elucidating the biological basis of complex traits such as blood pressure (BP). Although gene-by-environment interactions (G × E) have been previously shown to contribute to BP variation, their role in multi-ancestry cohorts remains underexplored. We hypothesize that G × E effects may explain additional variance in BP traits across diverse populations, where environmental exposures and genetic backgrounds are more heterogeneous. Here, we present an evaluation of the importance of G × E on systolic (SP), diastolic (DP), and pulse pressure (PP) in a multi-ancestry subset of 25,000 individuals from the UK Biobank. We considered 23 lifestyle variables as the environmental exposures, and estimated variance components attributed to demographics, population structure, genetic effects, environmental effects and geneby-environment interactions. Our results revealed that G × E accounts for 7% of variance in DP, 4% in SP, and 3% in PP. Notably, these estimates exceed those previously reported (2% for all BP traits) in a UK Biobank analysis restricted to White British individuals using similar lifestyle variables and methodology. However, accounting for G×E did not improve prediction accuracy in two cross-validation schemes. We also tried to uncover individual interactions affecting each trait by conducting G × E-GWAS. Although no interaction surpassed genome-wide significance, we annotated suggestive hits and uncovered genes enriched in blood pressure-relevant pathways. Our study suggests that environmental heterogeneity and diverse genetic backgrounds in multi-ancestry cohorts may amplify the role of G × E, underscoring the importance of diverse populations in capturing the full spectrum of trait architecture. Competing Interest Statement The authors have declared no competing interest. Funding Statement Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number R35GM146868 to FM. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This research was conducted using the UK Biobank Resource under application 62347 and all data collection was done by the Biobank prior to this project. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability The data used in our analyses are available from UK Biobank (https://www.ukbiobank.ac.uk).