{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T01:35:10Z","timestamp":1780536910336,"version":"3.54.1"},"reference-count":34,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2024,5,7]],"date-time":"2024-05-07T00:00:00Z","timestamp":1715040000000},"content-version":"vor","delay-in-days":41,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82071212"],"award-info":[{"award-number":["82071212"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81901181"],"award-info":[{"award-number":["81901181"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["12026414"],"award-info":[{"award-number":["12026414"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004826","name":"Beijing Natural Science Foundation","doi-asserted-by":"publisher","award":["JQ21022"],"award-info":[{"award-number":["JQ21022"]}],"id":[{"id":"10.13039\/501100004826","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,3,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Common genetic variants and susceptibility loci associated with Alzheimer\u2019s disease (AD) have been discovered through large-scale genome-wide association studies (GWAS), GWAS by proxy (GWAX) and meta-analysis of GWAS and GWAX (GWAS+GWAX). However, due to the very low repeatability of AD susceptibility loci and the low heritability of AD, these AD genetic findings have been questioned. We summarize AD genetic findings from the past 10\u00a0years and provide a new interpretation of these findings in the context of statistical heterogeneity. We discovered that only 17% of AD risk loci demonstrated reproducibility with a genome-wide significance of P\u2009&amp;lt;\u20095.00E-08 across all AD GWAS and GWAS+GWAX datasets. We highlighted that the AD GWAS+GWAX with the largest sample size failed to identify the most significant signals, the maximum number of genome-wide significant genetic variants or maximum heritability. Additionally, we identified widespread statistical heterogeneity in AD GWAS+GWAX datasets, but not in AD GWAS datasets. We consider that statistical heterogeneity may have attenuated the statistical power in AD GWAS+GWAX and may contribute to explaining the low repeatability (17%) of genome-wide significant AD susceptibility loci and the decreased AD heritability (40\u20132%) as the sample size increased. Importantly, evidence supports the idea that a decrease in statistical heterogeneity facilitates the identification of genome-wide significant genetic loci and contributes to an increase in AD heritability. Collectively, current AD GWAX and GWAS+GWAX findings should be meticulously assessed and warrant additional investigation, and AD GWAS+GWAX should employ multiple meta-analysis methods, such as random-effects inverse variance-weighted meta-analysis, which is designed specifically for statistical heterogeneity.<\/jats:p>","DOI":"10.1093\/bib\/bbae140","type":"journal-article","created":{"date-parts":[[2024,5,7]],"date-time":"2024-05-07T05:19:25Z","timestamp":1715059165000},"source":"Crossref","is-referenced-by-count":9,"title":["Interpretation of 10\u00a0years of Alzheimer\u2019s disease genetic findings in the perspective of statistical heterogeneity"],"prefix":"10.1093","volume":"25","author":[{"given":"Shan","family":"Gao","sequence":"first","affiliation":[{"name":"Beijing Institute of Brain Disorders , Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, , No. 10, Xitoutiao, You\u2019an Men Wai, Fengtai District, Beijing 100069, China"},{"name":"Capital Medical University , Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, , No. 10, Xitoutiao, You\u2019an Men Wai, Fengtai District, Beijing 100069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Wang","sequence":"additional","affiliation":[{"name":"Chinese Institute for Brain Research , No. 26, Kexueyuan Road, Changping District, Beijing 102206, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhifa","family":"Han","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences , No. 5, Dongdan Santichao, Dongcheng District, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4508-5365","authenticated-orcid":false,"given":"Yang","family":"Hu","sequence":"additional","affiliation":[{"name":"School of Computer Science and Technology, Harbin Institute of Technology , No. 92, Xidazhi Street, Nangang District, Harbin 150006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Zhu","sequence":"additional","affiliation":[{"name":"Beijing Institute of Brain Disorders , Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, , No. 10, Xitoutiao, You\u2019an Men Wai, Fengtai District, Beijing 100069, China"},{"name":"Capital Medical University , Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, , No. 10, Xitoutiao, You\u2019an Men Wai, Fengtai District, Beijing 100069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanli","family":"Xue","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering, Capital Medical University , No. 10 Xitoutiao, You'an Men Wai, Fengtai District, Beijing 100069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7092-7587","authenticated-orcid":false,"given":"Chen","family":"Huang","sequence":"additional","affiliation":[{"name":"Dr. Neher\u2019s Biophysics Laboratory for Innovative Drug Discovery , State Key Laboratory of Quality Research in Chinese Medicine, , Avenida WaiLong, Taipa 999078, Macao SAR, China"},{"name":"Macau University of Science and Technology , State Key Laboratory of Quality Research in Chinese Medicine, , Avenida WaiLong, Taipa 999078, Macao SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, School of Public Health, Wannan Medical College , No. 22, Wenchang Road, Wuhu 241002, Anhui, China"},{"name":"Institute of Chronic Disease Prevention and Control, Wannan Medical College , No. 22, Wenchang Road, Wuhu 241002, Anhui, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1126-2888","authenticated-orcid":false,"given":"Guiyou","family":"Liu","sequence":"additional","affiliation":[{"name":"Chinese Institute for Brain Research , No. 26, Kexueyuan Road, Changping District, Beijing 102206, China"},{"name":"Department of Epidemiology and Biostatistics, School of Public Health, Wannan Medical College , No. 22, Wenchang Road, Wuhu 241002, Anhui, China"},{"name":"Institute of Chronic Disease Prevention and Control, Wannan Medical College , No. 22, Wenchang Road, Wuhu 241002, Anhui, China"},{"name":"Key Laboratory of Cerebral Microcirculation in Universities of Shandong , Department of Neurology, , Taian 271000, Shandong, China"},{"name":"Second Affiliated Hospital, Shandong First Medical University and Shandong Academy of Medical Sciences , Department of Neurology, , Taian 271000, Shandong, China"},{"name":"Beijing Key Laboratory of Hypoxia Translational Medicine , National Engineering Laboratory of Internet Medical Diagnosis and Treatment Technology, , No. 45, Changchun Road, Xicheng District, Beijing 100053, China"},{"name":"Xuanwu Hospital, Capital Medical University , National Engineering Laboratory of Internet Medical Diagnosis and Treatment Technology, , No. 45, Changchun Road, Xicheng District, Beijing 100053, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,5,6]]},"reference":[{"key":"2024050705190273100_ref1","doi-asserted-by":"crossref","first-page":"1832","DOI":"10.1001\/jama.2010.574","article-title":"Genome-wide analysis of genetic loci associated with Alzheimer 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