Pleiotropic and sex-specific genetic mechanisms of circulating metabolic markers

Dennis 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 and Ole A. Andreassen ()
Additional contact information
Dennis Meer: University of Oslo and Oslo University Hospital
Zillur Rahman: University of Oslo and Oslo University Hospital
Aigar Ottas: Riia 23b
Pravesh Parekh: University of Oslo and Oslo University Hospital
Gleda Kutrolli: University of Oslo and Oslo University Hospital
Sara E. Stinson: University of Oslo and Oslo University Hospital
Maria Koromina: New York
Jaroslav Rokicki: Oslo University Hospital
Ida E. Sønderby: University of Oslo and Oslo University Hospital
Nadine Parker: University of Oslo and Oslo University Hospital
Markos Tesfaye: University of Oslo and Oslo University Hospital
Guy Hindley: University of Oslo and Oslo University Hospital
Linn N. Rødevand: University of Oslo and Oslo University Hospital
Elise Koch: University of Oslo and Oslo University Hospital
Nils Eiel Steen: University of Oslo and Oslo University Hospital
Jens Petter Berg: University of Oslo
Kevin S. O’Connell: University of Oslo and Oslo University Hospital
Olav B. Smeland: University of Oslo and Oslo University Hospital
Oleksandr Frei: University of Oslo and Oslo University Hospital
Anders M. Dale: University of California at San Diego
Srdjan Djurovic: University of Oslo and Oslo University Hospital
Kelli Lehto: Riia 23b
Maris Alver: Riia 23b
Lili Milani: Riia 23b
Alexey A. Shadrin: University of Oslo and Oslo University Hospital
Ole A. Andreassen: University of Oslo and Oslo University Hospital

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-60058-z

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