| Title: | Genetic underpinnings of the heterogeneous impact of obesity on lipid levels and cardiovascular disease |
| Journal: | Genome Medicine |
| Published: | 6 Oct 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41053791/ |
| DOI: | https://doi.org/10.1186/s13073-025-01522-9 |
| URL: | https://genomemedicine.biomedcentral.com/counter/pdf/10.1186/s13073-025-01522-9 |
Publication 19287
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Abstract
BackgroundObesity is thought to increase cardiovascular disease (CVD) risk partly through dyslipidemia. Yet, obesity's effects on dyslipidemia are not uniform. Understanding the shared genetic basis between obesity and lipid traits can provide insight into this heterogeneity and its implications for CVD risk.MethodsWe examined local genetic correlations between three lipid measures [high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), and triglycerides (TG)] and body mass index (BMI) using genome-wide association study summary statistics from European ancestry UK Biobank participants. We identified genomic loci with opposing genetic effects on obesity and dyslipidemia risk (protective BMI-lipid loci) and those with concordant directions for both obesity and dyslipidemia risk (adverse BMI-lipid loci). Gene-based association analyses were used to prioritize potential causal genes. We then constructed polygenic risk scores for BMI (PRSBMI) based on protective and adverse loci and assessed their associations with BMI, lipid levels, CVD, and related traits in the diverse Population Architecture using Genomics and Epidemiology (PAGE) study. PheWAS was performed in the All of Us cohort. Mendelian randomization (MR) was conducted to assess the causal impact of protective/adverse loci on cardiometabolic outcomes. Finally, we investigated the associations with fat distribution traits using MRI-based fat measures in the UK Biobank.ResultsAmong 2495 regions, we identified 789 HDL, 26 LDL, and 494 TG loci with significant local genetic correlation with BMI (including overlapping loci). Of these, 3 HDL, 10 LDL, and 8 TG loci showed protective correlations. Gene-based analyses prioritized 18 candidate causal genes. The protective PRSBMI(+)HDL(+) was associated with higher BMI but favorable lipid profiles and reduced CVD risk in PAGE. PheWAS revealed protective associations with hyperlipidemia, atrial fibrillation, and Alzheimer's disease. MR supported the favorable causal effects of these protective loci on several cardiometabolic outcomes. Notably, protective PRSBMI(+)TG(−) was uniquely associated with decreased visceral-to-abdominal subcutaneous adipose tissue ratio.ConclusionsIdentifying and validating genomic loci with shared genetic signals between BMI and lipid levels further supports the importance of genetics in defining the heterogeneous impact of obesity on dyslipidemia and CVD.</p>
14 Keywords
- Body Mass Index
- Cardiovascular Diseases
- Female
- Genetic Predisposition to Disease
- Genome-Wide Association Study
- Humans
- Lipids
- Male
- Mendelian Randomization Analysis
- Middle Aged
- Multifactorial Inheritance
- Obesity
- Polymorphism, Single Nucleotide
- Triglycerides
32 Authors
- Daeeun Kim
- Heather M. Highland
- Roelof A. J. Smit
- Micah R. Hysong
- Victoria L. Buchanan
- Kristin L. Young
- Chi Zhao
- Cassandra N. Spracklen
- Tuomas O. Kilpeläinen
- Boya Guo
- Burcu F. Darst
- Yanwei Cai
- Zhe Wang
- Jessica Lundin
- Sonja I. Berndt
- JoAnn E. Manson
- Eirini Marouli
- Leslie Lange
- Ethan Lange
- Myriam Fornage
- Christopher R. Gignoux
- Christopher A. Haiman
- Stephen S. Rich
- Steven Buyske
- Ruth J. F. Loos
- Charles Kooperberg
- Ulrike Peters
- Christy L. Avery
- Penny Gordon-Larsen
- Mariaelisa Graff
- Laura M. Raffield
- Kari E. North
1 Application
| Application ID | Title |
|---|---|
| 25953 | Transcriptome-wide Association Study of Cardiometabolic Traits in the UK Biobank Cohort |
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