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This exploratory study employed bidirectional Mendelian randomization (MR) analysis to investigate the causal relationships between MM and inflammatory diseases, including atherosclerosis, asthma, ankylosing spondylitis, Alzheimer's disease (AD), Parkinson's disease (PD), sarcoidosis, inflammatory bowel disease, nonalcoholic fatty liver disease, type II diabetes, and schizophrenia (SZ). Transcriptomic and genome\u2010wide Bayesian colocalization analyses were further applied to reveal the underlying mechanism. A significant and previously unrecognized positive association was identified between genetic predisposition to MM and the risk of SZ. Two independent case reports showed that treatment\u2010resistant psychosis is due to underlying MM and is resolved by treating MM. From our MR analyses, various statistical methods confirmed this association without detecting heterogeneity or pleiotropy effects. Transcriptomic analysis revealed shared inflammation\u2010relevant pathways in MM and SZ patients, suggesting inflammation as a potential pathophysiological mediator of MM's causal effect on SZ. Bayesian colocalization analysis identified rs9273086, which maps to the protein\u2010coding region of HLA\u2010DRB1, as a common risk variant for both MM and SZ. Polymorphism of the HLA\u2010DRB1 allele has been implicated in AD and PD, further highlighting the impact of our results. Additionally, we confirmed that interleukin\u20106 (IL\u20106) is a risk factor for SZ through secondary MR, reinforcing the role of neuroinflammation in SZ etiology. Overall, our findings showed that genetic predisposition to MM, HLA\u2010DRB1 polymorphism, and enhanced IL\u20106 signaling are associated with the increased risk of SZ, providing evidence for a causal role for neuroinflammation in SZ etiology.<\/jats:p>","DOI":"10.1002\/jha2.890","type":"journal-article","created":{"date-parts":[[2024,4,11]],"date-time":"2024-04-11T11:59:54Z","timestamp":1712836794000},"page":"462-473","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Multiple myeloma, IL6, and risk of schizophrenia: A Mendelian randomization, transcriptome, and Bayesian colocalization study"],"prefix":"10.1002","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9522-7798","authenticated-orcid":false,"given":"Shuyang","family":"Lin","sequence":"first","affiliation":[{"name":"Division of Hematology, Department of Medicine Washington University School of Medicine in St Louis  St Louis Missouri USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bei","family":"Gao","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomic Medicine, Department of Pediatrics Washington University School of Medicine in St. Louis  St Louis Missouri USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rui","family":"Xu","sequence":"additional","affiliation":[{"name":"Affiliated Cancer Hospital &amp; Institute of Guangzhou Medical University  Guangzhou Guangdong China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongming","family":"Shang","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana\u2010Farber Cancer Institute Harvard Medical School  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Xiong","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomic Medicine, Department of Pediatrics Washington University School of Medicine in St. Louis  St Louis Missouri USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiayi","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Hematology Fujian Medical University Union Hospital  Fuzhou Fujian China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhe","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Medicine Southern Medical University  Guangzhou Guangdong China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chao","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Cancer Center The People's Hospital of Baoan  Shenzhen Guangdong China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shumei","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Pathology, Sun Yat\u2010sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine Guangdong Provincial Clinical Research Center for Cancer  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,4,11]]},"reference":[{"key":"e_1_2_14_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/medsci9010003"},{"key":"e_1_2_14_3_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2022.0003"},{"key":"e_1_2_14_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.33762"},{"key":"e_1_2_14_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13045\u2010021\u201001116\u2010z"},{"key":"e_1_2_14_6_1","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyt.2018.00557"},{"key":"e_1_2_14_7_1","doi-asserted-by":"publisher","DOI":"10.1155\/2018\/974624"},{"key":"e_1_2_14_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjmed.2022.08.030"},{"key":"e_1_2_14_9_1","first-page":"43","article-title":"On the diagnosis of multiple myeloma an analysis of 2,547 domestic cases","volume":"17","author":"Li S","year":"1995","journal-title":"Chin J Cancer Res"},{"key":"e_1_2_14_10_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12893\u2010021\u201001377\u2010y"},{"key":"e_1_2_14_11_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2018.2128"},{"key":"e_1_2_14_12_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1903455"},{"key":"e_1_2_14_13_1","doi-asserted-by":"publisher","DOI":"10.2147\/tcrm.2006.2.3.271"},{"key":"e_1_2_14_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.26590"},{"key":"e_1_2_14_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.34214"},{"key":"e_1_2_14_16_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.886144"},{"key":"e_1_2_14_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41375\u2010021\u201001506\u20109"},{"key":"e_1_2_14_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41590\u2010021\u201000931\u20103"},{"key":"e_1_2_14_19_1","doi-asserted-by":"publisher","DOI":"10.1155\/2017\/1852517"},{"key":"e_1_2_14_20_1","doi-asserted-by":"publisher","DOI":"10.1017\/S0033291720005127"},{"key":"e_1_2_14_21_1","doi-asserted-by":"publisher","DOI":"10.12688\/wellcomeopenres.15555.3"},{"key":"e_1_2_14_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/s005350050385"},{"key":"e_1_2_14_23_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20236008"},{"issue":"7","key":"e_1_2_14_24_1","first-page":"726","article-title":"Association of ankylosing spondylitis with IgA\u2010multiple myeloma: report of a case and pathogenetic considerations","volume":"88","author":"Lam SM","year":"1989","journal-title":"Taiwan yi xue hui za zhi. 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