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The molecular mechanisms underlying treatment response heterogeneity are not well understood, and personalized treatment in BD remains elusive. Genetic analyses of the lithium treatment response phenotype may generate novel molecular insights into lithium\u2019s therapeutic mechanisms and lead to testable hypotheses to improve BD management and outcomes. We used fixed effect meta-analysis techniques to develop meta-analytic polygenic risk scores (MET-PRS) from combinations of highly correlated psychiatric traits, namely schizophrenia (SCZ), major depression (MD) and bipolar disorder (BD). We compared the effects of cross-disorder MET-PRS and single genetic trait PRS on lithium response. For the PRS analyses, we included clinical data on lithium treatment response and genetic information for<jats:italic>n<\/jats:italic>\u2009=\u20092283 BD cases from the International Consortium on Lithium Genetics (ConLi<jats:sup>+<\/jats:sup>Gen;<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/www.ConLiGen.org\">www.ConLiGen.org<\/jats:ext-link>). Higher SCZ and MD PRSs were associated with poorer lithium treatment response whereas BD-PRS had no association with treatment outcome. The combined MET2-PRS comprising of SCZ and MD variants (MET2-PRS) and a model using SCZ and MD-PRS sequentially improved response prediction, compared to single-disorder PRS or to a combined score using all three traits (MET3-PRS). Patients in the highest decile for MET2-PRS loading had 2.5 times higher odds of being classified as poor responders than patients with the lowest decile MET2-PRS scores. An exploratory functional pathway analysis of top MET2-PRS variants was conducted. Findings may inform the development of future testing strategies for personalized lithium prescribing in BD.<\/jats:p>","DOI":"10.1038\/s41398-021-01702-2","type":"journal-article","created":{"date-parts":[[2021,11,29]],"date-time":"2021-11-29T09:02:38Z","timestamp":1638176558000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":59,"title":["Combining schizophrenia and depression polygenic risk scores improves the genetic prediction of lithium response in bipolar disorder patients"],"prefix":"10.1038","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1690-0209","authenticated-orcid":false,"given":"Klaus 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EV has received grants and served as consultant, advisor or CME speaker for the following entities: AB-Biotics, Allergan, Angelini, AstraZeneca, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Farmindustria, Ferrer, Forest Research Institute, Gedeon Richter, Glaxo-Smith-Kline, Janssen, Lundbeck, Otsuka, Pfizer, Roche, Sanofi-Aventis, Servier, Shire, Sunovion, Takeda, the Brain and Behaviour Foundation, the Spanish Ministry of Science and Innovation (CIBERSAM), and the Stanley Medical Research Institute. MB has received grants from the Deutsche Forschungsgemeinschaft (DFG), and Bundesministeriums f\u00fcr Bildung und Forschung (BMBF), and served as consultant, advisor or CME speaker for the following entities: Allergan, Aristo, Janssen, Lilly, Lundbeck, neuraxpharm, Otsuka, Sandoz, Servier, and Sunovion outside the submitted work. SK-S has received grants and served as consultant, advisor or speaker for the following entities: Medice Arzneimittel P\u00fctter GmbH and Shire. BB has received grants and served as consultant, advisor or CME speaker for the following entities: AstraZeneca, Bristol-Myers Squibb, Janssen, Lundbeck, Otsuka, Servier, the National Health and Medical Research Council, the Fay Fuller Foundation, the James and Diana Ramsay Foundation. TK received honoraria for lectures, manuscripts, and\/or consultancy, from Kyowa Hakko Kirin Co., Ltd., Eli Lilly Japan K.K., Otsuka Pharmaceutical Co., Ltd., GlaxoSmithKline K.K., Taisho Toyama Pharmaceutical Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Meiji Seika Pharma Co., Ltd., Pfizer Japan Inc., Mochida Pharmaceutical Co., Ltd., Shionogi & Co., Ltd., Janssen Pharmaceutical K.K., Janssen Asia Pacific, Yoshitomiyakuhin, Astellas Pharma Inc., Wako Pure Chemical Industries, Ltd., Wiley Publishing Japan, Nippon Boehringer Ingelheim Co. Ltd., Kanae Foundation for the Promotion of Medical Science, MSD K.K., Kyowa Pharmaceutical Industry Co., Ltd. and Takeda Pharmaceutical Co., Ltd. TK also received a research grant from Takeda Pharmaceutical Co., Ltd. PF has received grants and served as consultant, advisor or CME speaker for the following entities Abbott, GlaxoSmithKline, Janssen, Essex, Lundbeck, Otsuka, Gedeon Richter, Servier and Takeda as well as the German Ministry of Science and the German Ministry of Health. ER has received grants and served as consultant, advisor or CME speaker for the following entities: Janssen and Institut Allergosan. ML declares that, over the past 36 months, he has received lecture honoraria from Lundbeck and served as a scientific consultant for EPID Research Oy; no other equity ownership, profit-sharing agreements, royalties, or patent. KA has received consulting honoraria from Taisho Toyama Pharmaceutical Co., Ltd. The remaining authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"606"}}