Whole-genome sequencing analyses suggest novel genetic factors associated with Alzheimer’s disease and a cumulative effects model for risk liability
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.
Authors
- Sang‐Hyuk Jung (ORCID: https://orcid.org/0000-0003-4116-3327)
- Jun Pyo Kim (ORCID: https://orcid.org/0000-0003-4376-3107)
- A-Hyun Cho (ORCID: https://orcid.org/0000-0003-2506-0408)
- Duk Lyul Na (ORCID: https://orcid.org/0000-0002-0098-7592)
- Hong‐Hee Won (ORCID: https://orcid.org/0000-0001-5719-0552)
- Joon‐Yong An (ORCID: https://orcid.org/0000-0001-8839-6297)
- Minyoung Cho (ORCID: https://orcid.org/0000-0001-5023-0902)
- C. A. Kim
- Young Chan Park (ORCID: https://orcid.org/0009-0009-1586-0082)
- Towfique Raj (ORCID: https://orcid.org/0000-0002-9355-5704)
- Beomjin Jang (ORCID: https://orcid.org/0009-0008-9056-1480)
- Beomsu Kim (ORCID: https://orcid.org/0000-0001-7410-4273)
- Hongki Ham (ORCID: https://orcid.org/0009-0002-0806-6453)
- Seoyeon Kim (ORCID: https://orcid.org/0000-0001-9184-7087)
- Hyemin Jang (ORCID: https://orcid.org/0000-0003-3152-1274)
- Eun Hye Lee (ORCID: https://orcid.org/0000-0002-4206-6214)
- In Gyeong Koh
- Hyun-Woo Lee (ORCID: https://orcid.org/0009-0003-7212-2162)
- Hee Jin Kim (ORCID: https://orcid.org/0000-0002-3186-9441)
- Jong‐Young Lee (ORCID: https://orcid.org/0000-0002-0092-9958)
- Jong Seung Kim (ORCID: https://orcid.org/0000-0003-3477-1172)
- Bo‐Hyun Kim (ORCID: https://orcid.org/0000-0003-2595-4890)
- Sang Won Seo (ORCID: https://orcid.org/0000-0003-2568-0797)
- Daeun Shin (ORCID: https://orcid.org/0000-0003-4834-1026)
Institutions
- Allen Institute for Brain Science (US)
- Kangwon National University (KR)
- Korea University (KR)
- Samsung (South Korea) (KR)
- Samsung Medical Center (KR)
- Seoul National University Hospital (KR)
- Korea National Institute of Health (KR)
- Hanmi Pharmaceutical (South Korea) (KR)
- Korea University (JP)
- Indiana University School of Medicine
- Indiana University – Purdue University Indianapolis (US)
- Sungkyunkwan University (KR)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-26
- DOI
- https://doi.org/10.1038/s41467-025-59949-y
- Citations
- 7
- Primary Topic
- Genomics and Rare Diseases
- Type
- article
- Field-Weighted Citation Impact
- 12.72
Funders
- National Research Foundation
- Korea University
- Ministry of Health and Welfare
- National Research Foundation of Korea
- National Center for Geriatrics and Gerontology
- Ministry of Science and ICT, South Korea
- Samsung
- Korea National Institute of Health
- Institute for Information and Communications Technology Promotion