{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T01:14:42Z","timestamp":1789175682786,"version":"build-2803163510"},"reference-count":41,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2024,12,10]],"date-time":"2024-12-10T00:00:00Z","timestamp":1733788800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2023YFC3605200"],"award-info":[{"award-number":["2023YFC3605200"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005089","name":"Natural Science Foundation of Beijing Municipality","doi-asserted-by":"publisher","award":["JQ21022"],"award-info":[{"award-number":["JQ21022"]}],"id":[{"id":"10.13039\/501100005089","id-type":"DOI","asserted-by":"publisher"}]},{"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":["82471449"],"award-info":[{"award-number":["82471449"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    To date, several studies have integrated genome\u2010wide association studies (GWAS) and expression quantitative trait loci (eQTL) data from bulk tissues to identify novel Alzheimer's disease (AD) genetic variants and susceptibility genes. However, there is highly cell\u2010type\u2010specific nature in different bulk eQTL data. Until now, eQTL data from different brain single cells have been reported. Therefore, integrating eQTL data from different brain single\u2010cell types along with AD GWAS data makes biological sense for studying the potential biological explanations of AD. Here, we utilized the summary\u2010data\u2010based Mendelian randomization (SMR) method to integrate AD GWAS data with eQTL data from eight brain single\u2010cell types. We identified a larger number of significant genes compared to previous SMR study based on bulk eQTL. Notably, microglia exhibited the highest number of significant genes. Moreover, we conducted validation\u2010phase SMR analysis, single\u2010cell analysis, protein\u2013protein interaction (PPI), druggability evaluation, functional enrichment analyses, and colocalization analysis of the top 20 SMR significant genes in microglia. We found that most genes passed the validation and were significantly enriched in microglia. PPI analysis uncovered interactions among PICALM, BIN1, RIN3, CD2AP, CASS4, and MS4A6E. Five most significant SMR genes were further validated through colocalization analysis. RIN3 is the only significant gene across all mentioned analyses and is a novel AD susceptibility gene at the genome\u2010wide significance level. Druggability evaluation identified KCNQ3, HLA\u2010DQB1, and RABEP1 as known genes previously targeted for drug development in neurological disorders, suggesting their potential therapeutic relevance in AD.\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc16276-fig-0006-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.16276","type":"journal-article","created":{"date-parts":[[2024,12,10]],"date-time":"2024-12-10T06:45:35Z","timestamp":1733813135000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Identification of Alzheimer's disease susceptibility genes by integrating eight human brain single\u2010cell transcriptomes with genome\u2010wide association studies"],"prefix":"10.1111","volume":"169","author":[{"given":"Yijie","family":"He","sequence":"first","affiliation":[{"name":"Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders Capital Medical University  Beijing 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 Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shan","family":"Gao","sequence":"additional","affiliation":[{"name":"Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiyang","family":"Wu","sequence":"additional","affiliation":[{"name":"Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuan","family":"Li","sequence":"additional","affiliation":[{"name":"Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Huang","sequence":"additional","affiliation":[{"name":"Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine Macau University of Science and Technology  Taipa 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  Wuhu 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":"Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders Capital Medical University  Beijing China"},{"name":"Department of Epidemiology and Biostatistics, School of Public Health Wannan Medical College  Wuhu China"},{"name":"Brain Hospital Shengli Oilfield Central Hospital  Dongying China"},{"name":"Beijing Key Laboratory of Hypoxia Translational Medicine, National Engineering Laboratory of Internet Medical Diagnosis and Treatment Technology, Xuanwu Hospital Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,12,10]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature15393"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-022-01024-z"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1003649"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-022-01128-z"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab447"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2004.02.027"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx1143"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-14457-z"},{"issue":"539","key":"e_1_2_11_10_1","first-page":"48","article-title":"Q\u2010value estimation for false discovery rate 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