Cardiometabolic disease and management of its risk factors, such as hypertension, dyslipidemia, adiposity and type II diabetes, constitute a major public health burden across diverse populations. Therefore, understanding the genetic and environmental (lifestyle) factors and their interactions (GxE) may provide insights into intervention, prevention and therapeutic strategies for addressing this burden. Several genome-wide association studies (GWAS) led by consortia such as CHARGE, ICBP and GIANT, among others, have revolutionized genetic discoveries for many complex traits by using ?genetic main effects? approaches. Despite increased attention to diversity in human genomics research, the number of GWAS in non-European populations is limited. The number of genome-wide interaction studies (GWIS) is also very limited. In contrast, the interplay between lifestyle/environment and genetics with an emphasis on diverse populations is a key part of the Precision Medicine Initiative (PMI) and the PMI Cohort targeting 1 million or more participants. The objective of this study is therefore to identify novel genetic loci associated with cardiometabolic traits, to investigate gene-lifestyle interactions through a focused study of the cardiometabolic trait loci, and to characterize the molecular effects underlying the interactions by leveraging existing ?omics? data such as DNA methylation, gene expression, and metabolites. By investigating genomic and environmental contributors to health outcomes across diverse populations, this proposal reflects the priorities of the PMI.
We propose to evaluate gene-lifestyle interactions across diverse populations (European, African, Hispanic, and Asian). Building on our current progress, we will expand the current focus on BP and lipids to include other cardiometabolic (adiposity and diabetes) traits; expand the currently dichotomized lifestyle factors (smoking, alcohol, physical activity, education, psychosocial, and sleep duration), by adding sleep duration, quantitative lifestyle exposures (e.g., cigarettes per day), and an Aggregate Lifestyle Index as an overall lifestyle risk factor for cardiometabolic health; and vastly increase the sample size to achieve greater statistical power. We will do this by adding substantially large existing studies to those currently participating in our projects. Our proposal includes the current discovery studies (N~130,000), the current replication studies (N~252,000), the Million Veteran Program (N~234,000), the UK Biobank (N~478,000), the Biobank Japan (N~160,000), and the Study of Latinos (N~13,000), among others. Overall sample size is 1.267 million, consisting of 912,000 European, 91,000 African, 33,000 Hispanic, and 231,000 Asian individuals. This would represent the most significant effort to date to investigate interactions with an aggregate sample size of about 1.267 million. Timely funding can sustain the great progress made during the current funding cycle, which may lead to new diagnostic and therapeutic tools, contribute to precision care in the management of cardiometabolic disorders, and provide insights for the PMI, thus potentially impacting clinical practice.
Funding:
Washington University School of Medicine in St. Louis
Funding Period:
04/27/2021 to 03/31/2025