학술논문
Combining schizophrenia and depression polygenic risk scores improves the genetic prediction of lithium response in bipolar disorder patients
Document Type
article
Author
Klaus Oliver Schubert; Anbupalam Thalamuthu; Azmeraw T. Amare; Joseph Frank; Fabian Streit; Mazda Adl; Nirmala Akula; Kazufumi Akiyama; Raffaella Ardau; Bárbara Arias; Jean-Michel Aubry; Lena Backlund; Abesh Kumar Bhattacharjee; Frank Bellivier; Antonio Benabarre; Susanne Bengesser; Joanna M. Biernacka; Armin Birner; Cynthia Marie-Claire; Micah Cearns; Pablo Cervantes; Hsi-Chung Chen; Caterina Chillotti; Sven Cichon; Scott R. Clark; Cristiana Cruceanu; Piotr M. Czerski; Nina Dalkner; Alexandre Dayer; Franziska Degenhardt; Maria Del Zompo; J. Raymond DePaulo; Bruno Étain; Peter Falkai; Andreas J. Forstner; Louise Frisen; Mark A. Frye; Janice M. Fullerton; Sébastien Gard; Julie S. Garnham; Fernando S. Goes; Maria Grigoroiu-Serbanescu; Paul Grof; Ryota Hashimoto; Joanna Hauser; Urs Heilbronner; Stefan Herms; Per Hoffmann; Liping Hou; Yi-Hsiang Hsu; Stephane Jamain; Esther Jiménez; Jean-Pierre Kahn; Layla Kassem; Po-Hsiu Kuo; Tadafumi Kato; John Kelsoe; Sarah Kittel-Schneider; Ewa Ferensztajn-Rochowiak; Barbara König; Ichiro Kusumi; Gonzalo Laje; Mikael Landén; Catharina Lavebratt; Marion Leboyer; Susan G. Leckband; Mario Maj; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium; Mirko Manchia; Lina Martinsson; Michael J. McCarthy; Susan McElroy; Francesc Colom; Marina Mitjans; Francis M. Mondimore; Palmiero Monteleone; Caroline M. Nievergelt; Markus M. Nöthen; Tomas Novák; Claire O’Donovan; Norio Ozaki; Urban Ösby; Sergi Papiol; Andrea Pfennig; Claudia Pisanu; James B. Potash; Andreas Reif; Eva Reininghaus; Guy A. Rouleau; Janusz K. Rybakowski; Martin Schalling; Peter R. Schofield; Barbara W. Schweizer; Giovanni Severino; Tatyana Shekhtman; Paul D. Shilling; Katzutaka Shimoda; Christian Simhandl; Claire M. Slaney; Alessio Squassina; Thomas Stamm; Pavla Stopkova; Fasil Tekola-Ayele; Alfonso Tortorella; Gustavo Turecki; Julia Veeh; Eduard Vieta; Stephanie H. Witt; Gloria Roberts; Peter P. Zandi; Martin Alda; Michael Bauer; Francis J. McMahon; Philip B. Mitchell; Thomas G. Schulze; Marcella Rietschel; Bernhard T. Baune
Source
Translational Psychiatry, Vol 11, Iss 1, Pp 1-8 (2021)
Subject
Language
English
ISSN
2158-3188
Abstract
Abstract 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.