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

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 Jang, Bo-Hyun Kim, Hongki Ham, Beomsu Kim, Yujin Kim, A-Hyun Cho, Towfique Raj, Hee Jin Kim, Duk L. Na, Sang Won Seo (), Joon-Yong An () and Hong-Hee Won ()
Additional contact information
Jun Pyo Kim: Samsung Medical Center
Minyoung Cho: Sungkyunkwan University
Chanhee Kim: Korea University
Hyunwoo Lee: Sungkyunkwan University
Beomjin Jang: Sungkyunkwan University
Sang-Hyuk Jung: Kangwon National University College of Medicine
Yujin Kim: Korea University
In Gyeong Koh: Korea University
Seoyeon Kim: Korea University
Daeun Shin: Samsung Medical Center
Eun Hye Lee: Sungkyunkwan University School of Medicine
Jong-Young Lee: Ltd
YoungChan Park: Korea National Institution of Health
Hyemin Jang: Samsung Medical Center
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
Hee Jin Kim: Samsung Medical Center
Duk L. Na: Samsung Medical Center
Sang Won Seo: Samsung Medical Center
Joon-Yong An: Korea University
Hong-Hee Won: Sungkyunkwan University

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-59949-y

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