[R01] Integrative approach to discover genes that disentangle obesity from cardiometabolic risk in a large multi-ancestry study

Ente: National Heart Lung and Blood Institute

Scadenza: 2031-02-28

Importo max: 856.812 EUR

Paese: US

Descrizione

Project Abstract Obesity is a major health burden and a risk factor for type-2-diabetes, hypertension and cardiovascular disease. However, 15-25% of individuals with obesity do not suffer from these complications- referred to as the metabolically healthy obese phenotype (MHO). There are also individuals with normal weight that are at a higher risk for cardiometabolic conditions- metabolically obesity normal weight (MONW). These observations highlight the heterogeneity in obesity and metabolic regulation, where not all individuals with obesity are at risk and not all individuals with normal weight are protected from cardiometabolic complications. The mechanisms that lead to this phenomenon are largely unknown. We hypothesize that the heterogeneity of obesity is suggestive of distinct genetic etiologies that govern obesity and propose to utilize the MHO/MONW paradox as a tool to identify genes and pathways that disentangle this relationship, which will advance our understanding of the genetic underpinnings of obesity. We have recently identified 62 genomic loci associated with increased risk of obesity and a protective effect on cardiometabolic traits using summary statistics of published data. Our hypothesis is further supported by our pilot study where we performed a genome-wide association study (GWAS) of 24 composite adiposity and cardiometabolic traits in 500,000 European individuals of the UK Biobank and identified 266 variants simultaneously associated with increased adiposity and lower cardiometabolic risk (proxy for MHO) or vice-versa. Our preliminary data already gave new biological insights revealing a different signature of tissue enrichment for MHO loci compared to obesity loci suggesting that they regulate body weight through different mechanisms. We also identified 8 genetic subtypes - each with a distinct association signature with disease outcomes providing the first critical steps to define subtypes of obesity. We propose to expand our discovery of MHO variants and conduct a multi-trait and multi-ancestry GWAS study of 24 adiposity and cardiometabolic traits in 1.3 million individuals (Aim 1a). We will then implement a multi-omic approach to prioritize candidate genes by co-localizing the identified MHO variants with transcriptomic, proteomic, and metabolomic data (Aim 1b). In addition to the common allelic spectrum, in (Aim 2), we aim to conduct an exome-wide search for rare coding variants associated with opposite effects on adiposity and cardiometabolic traits in 1.6 million individuals from the UK Biobank, All of Us, BioMe and BioVu data for which we already have access and are thus ideally suited to perform these analyses. In Aim 3, we will functionally characterize MHO candidate genes by performing targeted CRISPRi experiments in different cell types. Our proposal is innovative as it examines adiposity and cardiometabolic risk simultaneously in multi-trait analyses, integrates multiple layers of genomic data and technology, Istituzione: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI PI: Nathalie Chami Progetto: 1R01HL178985-01A1

Settori: National Heart Lung and Blood Institute

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