Multivariate genomic analysis of 5 million people elucidates the genetic architecture of shared components of the metabolic syndrome
Metabolic syndrome (MetS) is a complex hereditary condition comprising various metabolic traits as risk factors. Although the genetics of individual MetS components have been investigated actively through large-scale genome-wide association studies, the conjoint genetic architecture has not been fully elucidated. Here, we performed the largest multivariate genome-wide association study of MetS in Europe (n<sub>observed</sub> = 4,947,860) by leveraging genetic correlation between MetS components. We identified 1,307 genetic loci associated with MetS that were enriched primarily in brain tissues. Using transcriptomic data, we identified 11 genes associated strongly with MetS. Our phenome-wide association and Mendelian randomization analyses highlighted associations of MetS with diverse diseases beyond cardiometabolic diseases. Polygenic risk score analysis demonstrated better discrimination of MetS and predictive power in European and East Asian populations. Altogether, our findings will guide future studies aimed at elucidating the genetic architecture of MetS.
Authors
- Sang‐Hyuk Jung (ORCID: https://orcid.org/0000-0003-4116-3327)
- Woong‐Yang Park (ORCID: https://orcid.org/0000-0003-4234-0380)
- Ali Torkamani (ORCID: https://orcid.org/0000-0003-0232-8053)
- Chamlee Cho (ORCID: https://orcid.org/0009-0002-3155-1932)
- Woojae Myung (ORCID: https://orcid.org/0000-0001-9985-2032)
- Yeeun Ahn (ORCID: https://orcid.org/0000-0002-8584-5322)
- Minku Song
- Injeong Shim (ORCID: https://orcid.org/0000-0002-1001-0945)
- Hong‐Hee Won (ORCID: https://orcid.org/0000-0001-5719-0552)
- Pradeep Natarajan (ORCID: https://orcid.org/0000-0001-8402-7435)
- Soo‐Hyun Lim (ORCID: https://orcid.org/0000-0002-9578-4658)
- Tae Yang Yu (ORCID: https://orcid.org/0000-0003-0893-592X)
- Beomsu Kim (ORCID: https://orcid.org/0000-0001-7410-4273)
- Patrick T. Ellinor (ORCID: https://orcid.org/0000-0002-2067-0533)
- Dan Say Kim
- Akl C. Fahed (ORCID: https://orcid.org/0000-0002-4849-6389)
- Jaeyoung Kim (ORCID: https://orcid.org/0000-0001-6983-7907)
- Soyeon Kim (ORCID: https://orcid.org/0000-0002-2798-2257)
- Hyejin Kim (ORCID: https://orcid.org/0000-0002-5446-0358)
- Sanghyeon Park (ORCID: https://orcid.org/0000-0002-9854-0085)
- Sanghoon Hong
- Hyeonbin Jo
Institutions
- Broad Institute (US)
- Scripps Research Institute (US)
- Harvard University (US)
- Samsung Medical Center (KR)
- Seoul National University Bundang Hospital (KR)
- Massachusetts General Hospital (US)
- Wonkwang University Hospital (KR)
- National University College (PR)
- University of Pennsylvania (US)
- Sungkyunkwan University (KR)
Publication Details
- Journal
- Nature Genetics
- Published
- 2024-09-30
- DOI
- https://doi.org/10.1038/s41588-024-01933-1
- Citations
- 53
- Primary Topic
- Genetic Associations and Epidemiology
- Type
- article
- Field-Weighted Citation Impact
- 29.17
Funders
- Korea Disease Control and Prevention Agency
- National Research Foundation
- National Research Foundation of Korea