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Functional variants identify sex-specific genes and pathways in Alzheimer’s Disease

Author

Listed:
  • Thomas Bourquard

    (Baylor College of Medicine)

  • Kwanghyuk Lee

    (Baylor College of Medicine)

  • Ismael Al-Ramahi

    (Baylor College of Medicine
    Texas Children’s Hospital
    Baylor College of Medicine)

  • Minh Pham

    (Baylor College of Medicine)

  • Dillon Shapiro

    (Baylor College of Medicine)

  • Yashwanth Lagisetty

    (Baylor College of Medicine
    UTHealth McGovern Medical School)

  • Shirin Soleimani

    (Baylor College of Medicine)

  • Samantha Mota

    (Baylor College of Medicine)

  • Kevin Wilhelm

    (Baylor College of Medicine)

  • Maryam Samieinasab

    (Baylor College of Medicine)

  • Young Won Kim

    (Baylor College of Medicine)

  • Eunna Huh

    (Baylor College of Medicine)

  • Jennifer Asmussen

    (Baylor College of Medicine)

  • Panagiotis Katsonis

    (Baylor College of Medicine)

  • Juan Botas

    (Baylor College of Medicine
    Texas Children’s Hospital
    Baylor College of Medicine)

  • Olivier Lichtarge

    (Baylor College of Medicine
    Baylor College of Medicine
    Baylor College of Medicine)

Abstract

The incidence of Alzheimer’s Disease in females is almost double that of males. To search for sex-specific gene associations, we build a machine learning approach focused on functionally impactful coding variants. This method can detect differences between sequenced cases and controls in small cohorts. In the Alzheimer’s Disease Sequencing Project with mixed sexes, this approach identified genes enriched for immune response pathways. After sex-separation, genes become specifically enriched for stress-response pathways in male and cell-cycle pathways in female. These genes improve disease risk prediction in silico and modulate Drosophila neurodegeneration in vivo. Thus, a general approach for machine learning on functionally impactful variants can uncover sex-specific candidates towards diagnostic biomarkers and therapeutic targets.

Suggested Citation

  • Thomas Bourquard & Kwanghyuk Lee & Ismael Al-Ramahi & Minh Pham & Dillon Shapiro & Yashwanth Lagisetty & Shirin Soleimani & Samantha Mota & Kevin Wilhelm & Maryam Samieinasab & Young Won Kim & Eunna H, 2023. "Functional variants identify sex-specific genes and pathways in Alzheimer’s Disease," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38374-z
    DOI: 10.1038/s41467-023-38374-z
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    References listed on IDEAS

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