Combining schizophrenia and depression polygenic risk scores improves the genetic prediction of lithium response in bipolar disorder patients
Authors: Schubert Klaus Oliver , Thalamuthu Anbupalam , Amare Azmeraw T. , Frank Joseph , Streit Fabian , Adl Mazda , Akula Nirmala , Akiyama Kazufumi , Ardau Raffaella , Arias Bárbara , Aubry Jean-Michel , Backlund Lena , Bhattacharjee Abesh Kumar , Bellivier Frank , Benabarre Antonio , Bengesser Susanne , Biernacka Joanna M. , Birner Armin , Marie-Claire Cynthia , Cearns Micah , Cervantes Pablo , Chen Hsi-Chung , Chillotti Caterina , Cichon Sven , Clark Scott R. , Cruceanu Cristiana , Czerski Piotr M. , Dalkner Nina , Dayer Alexandre , Degenhardt Franziska , Del Zompo Maria , DePaulo J. Raymond , Étain Bruno , Falkai Peter , Forstner Andreas J. , Frisen Louise , Frye Mark A. , Fullerton Janice M. , Gard Sébastien , Garnham Julie S. , Goes Fernando S. , Grigoroiu-Serbanescu Maria , Grof Paul , Hashimoto Ryota , Hauser Joanna , Heilbronner Urs , Herms Stefan , Hoffmann Per , Hou Liping , Hsu Yi-Hsiang , Jamain Stephane , Jiménez Esther , Kahn Jean-Pierre , Kassem Layla , Kuo Po-Hsiu , Kato Tadafumi , Kelsoe John , Kittel-Schneider Sarah , Ferensztajn-Rochowiak Ewa , König Barbara , Kusumi Ichiro , Laje Gonzalo , Landén Mikael , Lavebratt Catharina , Leboyer Marion , Leckband Susan G. , Maj Mario ,   Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Manchia Mirko , Martinsson Lina , McCarthy Michael J. , McElroy Susan , Colom Francesc , Mitjans Marina , Mondimore Francis M. , Monteleone Palmiero , Nievergelt Caroline M. , Nöthen Markus M. , Novák Tomas , O’Donovan Claire , Ozaki Norio , Ösby Urban , Papiol Sergi , Pfennig Andrea , Pisanu Claudia , Potash James B. , Reif Andreas , Reininghaus Eva , Rouleau Guy A. , Rybakowski Janusz K. , Schalling Martin , Schofield Peter R. , Schweizer Barbara W. , Severino Giovanni , Shekhtman Tatyana , Shilling Paul D. , Shimoda Katzutaka , Simhandl Christian , Slaney Claire M. , Squassina Alessio , Stamm Thomas , Stopkova Pavla , Tekola-Ayele Fasil , Tortorella Alfonso , Turecki Gustavo , Veeh Julia , Vieta Eduard , Witt Stephanie H. , Roberts Gloria , Zandi Peter P. , Alda Martin , Bauer Michael , McMahon Francis J. , Mitchell Philip B. , Schulze Thomas G. , Rietschel Marcella , Baune Bernhard T. 
Published: November 2021

Lithium is the gold standard therapy for Bipolar Disorder (BD) but its effectiveness differs widely between individuals. 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’s 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 forn = 2283 BD cases from the International Consortium on Lithium Genetics (ConLi+Gen;www.ConLiGen.org). 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.