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Pleiotropic and sex-specific genetic mechanisms of circulating metabolic markers

Author

Listed:
  • 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
    New York
    New York)

  • Jaroslav Rokicki

    (Oslo University Hospital)

  • Ida E. Sønderby

    (University of Oslo and Oslo University Hospital
    Oslo University Hospital and University of Oslo
    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
    University of Bergen)

  • Guy Hindley

    (University of Oslo and Oslo University Hospital
    King’s College London)

  • 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
    Diakonhjemmet 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
    University of Oslo)

  • Anders M. Dale

    (University of California at San Diego)

  • Srdjan Djurovic

    (University of Oslo and Oslo University Hospital
    Oslo University Hospital and University of Oslo)

  • Kelli Lehto

    (Riia 23b)

  • Maris Alver

    (Riia 23b)

  • Lili Milani

    (Riia 23b)

  • Alexey A. Shadrin

    (University of Oslo and Oslo University Hospital
    University of Oslo and Oslo University Hospital)

  • Ole A. Andreassen

    (University of Oslo and Oslo University Hospital
    University of Oslo and Oslo University Hospital)

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.

Suggested Citation

  • 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 & Lin, 2025. "Pleiotropic and sex-specific genetic mechanisms of circulating metabolic markers," Nature Communications, Nature, vol. 16(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60058-z
    DOI: 10.1038/s41467-025-60058-z
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