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Whole-exome sequencing identifies protein-coding variants associated with brain iron in 29,828 individuals

Author

Listed:
  • Weikang Gong

    (Fudan University
    University of Oxford)

  • Yan Fu

    (Qingdao University)

  • Bang-Sheng Wu

    (Fudan University)

  • Jingnan Du

    (Harvard University)

  • Liu Yang

    (Fudan University)

  • Ya-Ru Zhang

    (Fudan University)

  • Shi-Dong Chen

    (Fudan University)

  • JuJiao Kang

    (Fudan University
    Fudan University)

  • Ying Mao

    (Fudan University)

  • Qiang Dong

    (Fudan University)

  • Lan Tan

    (Qingdao University)

  • Jianfeng Feng

    (Fudan University
    Fudan University
    University of Warwick)

  • Wei Cheng

    (Fudan University
    Fudan University
    Fudan University)

  • Jin-Tai Yu

    (Fudan University)

Abstract

Iron plays a fundamental role in multiple brain disorders. However, the genetic underpinnings of brain iron and its implications for these disorders are still lacking. Here, we conduct an exome-wide association analysis of brain iron, measured by quantitative susceptibility mapping technique, across 26 brain regions among 26,789 UK Biobank participants. We find 36 genes linked to brain iron, with 29 not being previously reported, and 16 of them can be replicated in an independent dataset with 3,039 subjects. Many of these genes are involved in iron transport and homeostasis, such as FTH1 and MLX. Several genes, while not previously connected to brain iron, are associated with iron-related brain disorders like Parkinson’s (STAB1, KCNA10), Alzheimer’s (SHANK1), and depression (GFAP). Mendelian randomization analysis reveals six causal relationships from regional brain iron to brain disorders, such as from the hippocampus to depression and from the substantia nigra to Parkinson’s. These insights advance our understanding of the genetic architecture of brain iron and offer potential therapeutic targets for brain disorders.

Suggested Citation

  • Weikang Gong & Yan Fu & Bang-Sheng Wu & Jingnan Du & Liu Yang & Ya-Ru Zhang & Shi-Dong Chen & JuJiao Kang & Ying Mao & Qiang Dong & Lan Tan & Jianfeng Feng & Wei Cheng & Jin-Tai Yu, 2024. "Whole-exome sequencing identifies protein-coding variants associated with brain iron in 29,828 individuals," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49702-2
    DOI: 10.1038/s41467-024-49702-2
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