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Whole-genome sequencing analyses suggest novel genetic factors associated with Alzheimer’s disease and a cumulative effects model for risk liability

Author

Listed:
  • Jun Pyo Kim

    (Samsung Medical Center
    Sungkyunkwan University School of Medicine
    Samsung Medical Center)

  • Minyoung Cho

    (Sungkyunkwan University)

  • Chanhee Kim

    (Korea University
    Korea University)

  • Hyunwoo Lee

    (Sungkyunkwan University)

  • Beomjin Jang

    (Sungkyunkwan University
    Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Sang-Hyuk Jung

    (Kangwon National University College of Medicine)

  • Yujin Kim

    (Korea University
    Korea University)

  • In Gyeong Koh

    (Korea University
    Korea University)

  • Seoyeon Kim

    (Korea University
    Korea University)

  • Daeun Shin

    (Samsung Medical Center
    Sungkyunkwan University School of Medicine
    Samsung Medical Center)

  • Eun Hye Lee

    (Sungkyunkwan University School of Medicine
    Indiana University School of Medicine
    Indiana University School of Medicine)

  • Jong-Young Lee

    (Ltd)

  • YoungChan Park

    (Korea National Institution of Health)

  • Hyemin Jang

    (Samsung Medical Center
    Seoul National University School of Medicine)

  • Bo-Hyun Kim

    (Samsung Medical Center)

  • Hongki Ham

    (Sungkyunkwan University School of Medicine)

  • Beomsu Kim

    (Sungkyunkwan University)

  • Yujin Kim

    (Sungkyunkwan University)

  • A-Hyun Cho

    (Sungkyunkwan University)

  • Towfique Raj

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Hee Jin Kim

    (Samsung Medical Center
    Sungkyunkwan University School of Medicine
    Samsung Medical Center)

  • Duk L. Na

    (Samsung Medical Center
    Sungkyunkwan University School of Medicine
    Samsung Medical Center)

  • Sang Won Seo

    (Samsung Medical Center
    Sungkyunkwan University School of Medicine
    Samsung Medical Center
    Sungkyunkwan University)

  • Joon-Yong An

    (Korea University
    Korea University
    Korea University)

  • Hong-Hee Won

    (Sungkyunkwan University
    Samsung Medical Center)

Abstract

Genome-wide association studies (GWAS) on Alzheimer’s disease (AD) have predominantly focused on identifying common variants in Europeans. Here, we performed whole-genome sequencing (WGS) of 1,559 individuals from a Korean AD cohort to identify various genetic variants and biomarkers associated with AD. Our GWAS analysis identified a previously unreported locus for common variants (APCDD1) associated with AD. Our WGS analysis was extended to explore the less-characterized genetic factors contributing to AD risk. We identified rare noncoding variants located in cis-regulatory elements specific to excitatory neurons associated with cognitive impairment. Moreover, structural variation analysis showed that short tandem repeat expansion was associated with an increased risk of AD, and copy number variant at the HPSE2 locus showed borderline statistical significance. APOE ε4 carriers with high polygenic burden or structural variants exhibited severe cognitive impairment and increased amyloid beta levels, suggesting a cumulative effects model of AD risk.

Suggested Citation

  • Jun Pyo Kim & Minyoung Cho & Chanhee Kim & Hyunwoo Lee & Beomjin Jang & Sang-Hyuk Jung & Yujin Kim & In Gyeong Koh & Seoyeon Kim & Daeun Shin & Eun Hye Lee & Jong-Young Lee & YoungChan Park & Hyemin J, 2025. "Whole-genome sequencing analyses suggest novel genetic factors associated with Alzheimer’s disease and a cumulative effects model for risk liability," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59949-y
    DOI: 10.1038/s41467-025-59949-y
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