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Alzheimer’s disease genome-wide association studies in the context of statistical heterogeneity

Molecular Psychiatry (2024)Cite this article

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Alzheimer’s disease (AD) is the most common neurodegenerative disease in the elderly [1,2,3]. In recent years, large-scale AD genome-wide association studies (GWAS) have identified some novel AD genetic variants [1,2,3,4,5,6,7,8,9,10,11,12]. However, most of these AD GWAS are based on the European ancestry individuals [1,2,3,4,5,6,7,8,9,10,11,12]. Until recently, Lake and colleagues conducted the largest multi-ancestry meta-analysis of AD and related dementias using multiple AD GWAS and GWAS by disease proxy (GWAX) datasets from European (39,106 clinically diagnosed AD, 46,828 proxy-AD and related dementia and 401,577 controls; 7329 AD and 131,102 controls), East Asian (3962 AD and 4074 controls), African American (2748 AD and 5222 controls), and Caribbean Hispanic (1095 AD and 1179 controls) populations [13].

Lake and colleagues selected three methods including fixed-effects model meta-analysis, random-effects model meta-analysis, and multi-ancestry meta-regression to integrate these five GWAS and/or GWAX summary statistics [13]. They identified 48, 51, and 58 genome-wide significant loci using fixed-effects model, random-effects model, and multi-ancestry meta-regression, respectively [13]. Most loci overlapped across these three methods but 7 loci including 5 only significant using fixed-effects model (ADAMTS1, MAF, PLEKHA1, TSPOAP1, and UMAD1), 1 only significant using random-effects model (KANSL1), and 1 only significant using multi-ancestry meta-regression (JAZF1) [13]. Finally, Lake and colleagues identified a total of 68 genome-wide significant loci (P < 5.00E−08) including 66 known loci and two novel loci on chromosome 3 near TRANK1 (rs9867455) and VWA5B2 (rs9837978) [13]. These findings highlighted the importance of multi-ancestry GWAS meta-analysis of AD and related dementias.

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Acknowledgements

This work was supported by funding from the Beijing Natural Science Foundation (Grant No. JQ21022), National Natural Science Foundation of China (Grant No. 82071212, 81901181, and 12026414), and Beijing Ten Thousand Talents Project (Grant No. 2020A15). This work was also partially supported by funding from the Science and Technology Beijing One Hundred Leading Talent Training Project (Z141107001514006), the Beijing Municipal Administration of Hospitals’ Mission Plan (SML20150802), the Funds of Academic Promotion Programme of Shandong First Medical University & Shandong Academy of Medical Sciences (No. 2019QL016, No. 2019PT007).

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Author notes

  1. These authors contributed equally: Shan Gao, Ping Zhu, Tao Wang

Authors and Affiliations

  1. Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Capital Medical University, 100069, Beijing, China

    Shan Gao, Ping Zhu, Haihua Zhang & Guiyou Liu

  2. Chinese Institute for Brain Research, 102206, Beijing, China

    Tao Wang & Guiyou Liu

  3. Center of Respiratory Medicine, China-Japan Friendship Hospital, National Center for Respiratory Medicine, Institute of Respiratory Medicine, Chinese Acadamy of Medical Sciences, National Clinical Research Center for Respiratory Diseases, 100029, Beijing, China

    Zhifa Han

  4. School of Biomedical Engineering, Capital Medical University, 10069, Beijing, China

    Yanli Xue

  5. Department of Pathology, The Affiliated Hospital of Weifang Medical University, Weifang, 261053, China

    Yan Zhang

  6. Department of Anesthesiology, The Affiliated Hospital of Weifang Medical University, Weifang, 261053, China

    Longcai Wang

  7. Department of Epidemiology and Biostatistics, School of Public Health, Wannan Medical College, No. 22, Wenchang Road, Wuhu, 241002, Anhui, China

    Yan Chen & Guiyou Liu

  8. Institute of Chronic Disease Prevention and Control, Wannan Medical College, No.22, Wenchang Road, Wuhu, 241002, Anhui, China

    Yan Chen & Guiyou Liu

  9. Beijing Key Laboratory of Hypoxia Translational Medicine, Beijing Key Laboratory of Translational Medicine for Cerebrovascular Diseases, National Engineering Laboratory of Internet Medical Diagnosis and Treatment Technology, Xuanwu Hospital, Capital Medical University, 100053, Beijing, China

    Guiyou Liu

  10. Brain Hospital, Shengli Oilfield Central Hospital, Dongying, 257000, Shandong, China

    Guiyou Liu

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  1. Shan Gao
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Contributions

GYL designed the study; GYL, TW, ZFH and SG analyzed the data; all authors contributed to the interpretation of the results and critical revision of the manuscript for important intellectual content and approved the final version of the manuscript.

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Correspondence to Guiyou Liu.

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Gao, S., Zhu, P., Wang, T. et al. Alzheimer’s disease genome-wide association studies in the context of statistical heterogeneity. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02654-x

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