Whole-genome sequencing analyses suggest novel genetic factors associated with Alzheimer’s disease and a cumulative effects model for risk liability
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 associ...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59949-y |
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| author | 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 Hong-Hee Won |
| author_facet | 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 Hong-Hee Won |
| author_sort | Jun Pyo Kim |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-c64295ade9b445258a919e47d8cd6a1c |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-c64295ade9b445258a919e47d8cd6a1c2025-08-20T03:22:07ZengNature PortfolioNature Communications2041-17232025-05-0116111810.1038/s41467-025-59949-yWhole-genome sequencing analyses suggest novel genetic factors associated with Alzheimer’s disease and a cumulative effects model for risk liabilityJun Pyo Kim0Minyoung Cho1Chanhee Kim2Hyunwoo Lee3Beomjin Jang4Sang-Hyuk Jung5Yujin Kim6In Gyeong Koh7Seoyeon Kim8Daeun Shin9Eun Hye Lee10Jong-Young Lee11YoungChan Park12Hyemin Jang13Bo-Hyun Kim14Hongki Ham15Beomsu Kim16Yujin Kim17A-Hyun Cho18Towfique Raj19Hee Jin Kim20Duk L. Na21Sang Won Seo22Joon-Yong An23Hong-Hee Won24Alzheimer’s Disease Convergence Research Center, Samsung Medical CenterDepartment of Digital Health, Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Sungkyunkwan UniversityDepartment of Integrated Biomedical and Life Science, Korea UniversityDepartment of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Sungkyunkwan UniversityDepartment of Digital Health, Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Sungkyunkwan UniversityDepartment of Medical Informatics, Kangwon National University College of MedicineDepartment of Integrated Biomedical and Life Science, Korea UniversityDepartment of Integrated Biomedical and Life Science, Korea UniversityDepartment of Integrated Biomedical and Life Science, Korea UniversityAlzheimer’s Disease Convergence Research Center, Samsung Medical CenterDepartment of Neurology, Samsung Medical Center, Sungkyunkwan University School of MedicineOneomics Co., LtdDivision of Bio Bigdata, Department of Precision Medicine, Korea National Institution of HealthAlzheimer’s Disease Convergence Research Center, Samsung Medical CenterAlzheimer’s Disease Convergence Research Center, Samsung Medical CenterDepartment of Neurology, Samsung Medical Center, Sungkyunkwan University School of MedicineDepartment of Digital Health, Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Sungkyunkwan UniversityDepartment of Digital Health, Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Sungkyunkwan UniversityDepartment of Digital Health, Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Sungkyunkwan UniversityDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount SinaiAlzheimer’s Disease Convergence Research Center, Samsung Medical CenterAlzheimer’s Disease Convergence Research Center, Samsung Medical CenterAlzheimer’s Disease Convergence Research Center, Samsung Medical CenterDepartment of Integrated Biomedical and Life Science, Korea UniversityDepartment of Digital Health, Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Sungkyunkwan UniversityAbstract 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.https://doi.org/10.1038/s41467-025-59949-y |
| spellingShingle | 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 Hong-Hee Won Whole-genome sequencing analyses suggest novel genetic factors associated with Alzheimer’s disease and a cumulative effects model for risk liability Nature Communications |
| title | Whole-genome sequencing analyses suggest novel genetic factors associated with Alzheimer’s disease and a cumulative effects model for risk liability |
| title_full | Whole-genome sequencing analyses suggest novel genetic factors associated with Alzheimer’s disease and a cumulative effects model for risk liability |
| title_fullStr | Whole-genome sequencing analyses suggest novel genetic factors associated with Alzheimer’s disease and a cumulative effects model for risk liability |
| title_full_unstemmed | Whole-genome sequencing analyses suggest novel genetic factors associated with Alzheimer’s disease and a cumulative effects model for risk liability |
| title_short | Whole-genome sequencing analyses suggest novel genetic factors associated with Alzheimer’s disease and a cumulative effects model for risk liability |
| title_sort | whole genome sequencing analyses suggest novel genetic factors associated with alzheimer s disease and a cumulative effects model for risk liability |
| url | https://doi.org/10.1038/s41467-025-59949-y |
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