| Title: | Pleiotropic and sex-specific genetic mechanisms of circulating metabolic markers |
| Journal: | Nature Communications |
| Published: | 28 May 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/40436851/ |
| DOI: | https://doi.org/10.1038/s41467-025-60058-z |
| URL: | https://www.nature.com/articles/s41467-025-60058-z.pdf |
Publication 15198
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Abstract
Metabolites in plasma form biosignatures of a range of common complex human diseases. Discovering variants with pleiotropic effects across metabolites can reveal underlying biological mechanisms. We therefore performed uni- and multivariate genome-wide association studies (GWAS) on 249 circulating metabolic markers across 328,006 UK Biobank and Estonian Biobank participants. We investigated rare variation through whole exome sequencing gene burden tests, analysed the role of body mass index through Mendelian randomization, and performed genome-wide interaction analyses with sex. We discovered 15,585 loci summed over the univariate GWAS, with high pleiotropy across markers, linked to a wide range of disorders. Findings from common and rare variant gene tests converged on lipid homeostasis pathways. 31 loci interacted with sex, mapped to genes involved in cholesterol processing. The findings offer insights into the genetic architecture of circulating metabolites, revealing pleiotropic loci, highlighting the role of rare variation, and uncovering sex-specific molecular mechanisms of lipid metabolism.</p>
16 Keywords
- Biomarkers
- Body Mass Index
- Cholesterol
- Estonia
- Exome Sequencing
- Female
- Genetic Pleiotropy
- Genome-Wide Association Study
- Humans
- Lipid Metabolism
- Male
- Mendelian Randomization Analysis
- Middle Aged
- Polymorphism, Single Nucleotide
- Sex Factors
- United Kingdom
26 Authors
- Dennis van der Meer
- Zillur Rahman
- Aigar Ottas
- Pravesh Parekh
- Gleda Kutrolli
- Sara E. Stinson
- Maria Koromina
- Jaroslav Rokicki
- Ida E. Sønderby
- Nadine Parker
- Markos Tesfaye
- Guy Hindley
- Linn N. Rødevand
- Elise Koch
- Nils Eiel Steen
- Jens Petter Berg
- Kevin S. O'Connell
- Olav B. Smeland
- Oleksandr Frei
- Anders M. Dale
- Srdjan Djurovic
- Kelli Lehto
- Maris Alver
- Lili Milani
- Alexey A. Shadrin
- Ole A. Andreassen
1 Application
| Application ID | Title |
|---|---|
| 27412 | Boosting the power of GWAS using novel statistical tools |
Enabling scientific discoveries that improve human health