TY - JOUR
T1 - Combining schizophrenia and depression polygenic risk scores improves the genetic prediction of lithium response in bipolar disorder patients
AU - Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium
AU - Schubert, Klaus Oliver
AU - Thalamuthu, Anbupalam
AU - Amare, Azmeraw T.
AU - Frank, Joseph
AU - Streit, Fabian
AU - Adl, Mazda
AU - Akula, Nirmala
AU - Akiyama, Kazufumi
AU - Ardau, Raffaella
AU - Arias, Bárbara
AU - Aubry, Jean Michel
AU - Backlund, Lena
AU - Bhattacharjee, Abesh Kumar
AU - Bellivier, Frank
AU - Benabarre, Antonio
AU - Bengesser, Susanne
AU - Biernacka, Joanna M.
AU - Birner, Armin
AU - Marie-Claire, Cynthia
AU - Cearns, Micah
AU - Cervantes, Pablo
AU - Chen, Hsi Chung
AU - Chillotti, Caterina
AU - Cichon, Sven
AU - Clark, Scott R.
AU - Cruceanu, Cristiana
AU - Czerski, Piotr M.
AU - Dalkner, Nina
AU - Dayer, Alexandre
AU - Degenhardt, Franziska
AU - Del Zompo, Maria
AU - DePaulo, J. Raymond
AU - Étain, Bruno
AU - Falkai, Peter
AU - Forstner, Andreas J.
AU - Frisen, Louise
AU - Frye, Mark A.
AU - Fullerton, Janice M.
AU - Gard, Sébastien
AU - Garnham, Julie S.
AU - Goes, Fernando S.
AU - Grigoroiu-Serbanescu, Maria
AU - Grof, Paul
AU - Hashimoto, Ryota
AU - Hauser, Joanna
AU - Heilbronner, Urs
AU - Herms, Stefan
AU - Hoffmann, Per
AU - Hou, Liping
AU - Hsu, Yi Hsiang
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - 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 for n = 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.
AB - 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 for n = 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85120159497&partnerID=8YFLogxK
U2 - 10.1038/s41398-021-01702-2
DO - 10.1038/s41398-021-01702-2
M3 - Article
C2 - 34845190
AN - SCOPUS:85120159497
SN - 2158-3188
VL - 11
JO - Translational psychiatry
JF - Translational psychiatry
IS - 1
M1 - 606
ER -