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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.

Titel:	Combining schizophrenia and depression polygenic risk scores improves the genetic prediction of lithium response in bipolar disorder patients.
Autor/in / Beteiligte Person:	Schubert, KO ; Thalamuthu, A ; Amare, AT ; Frank, J ; Streit, F ; Adl, M ; Akula, N ; Akiyama, K ; Ardau, R ; Arias, B ; Aubry, JM ; Backlund, L ; Bhattacharjee, AK ; Bellivier, F ; Benabarre, A ; Bengesser, S ; Biernacka, JM ; Birner, A ; Marie-Claire, C ; Cearns, M ; Cervantes, P ; Chen, HC ; Chillotti, C ; Cichon, S ; Clark, SR ; Cruceanu, C ; Czerski, PM ; Dalkner, N ; Dayer, A ; Degenhardt, F ; Del Zompo, M ; DePaulo, JR ; Étain, B ; Falkai, P ; Forstner, AJ ; Frisen, L ; Frye, MA ; Fullerton, JM ; Gard, S ; Garnham, JS ; Goes, FS ; Grigoroiu-Serbanescu, M ; Grof, P ; Hashimoto, R ; Hauser, J ; Heilbronner, U ; Herms, S ; Hoffmann, P ; Hou, L ; Hsu, YH ; Jamain, S ; Jiménez, E ; Kahn, JP ; Kassem, L ; Kuo, PH ; Kato, T ; Kelsoe, J ; Kittel-Schneider, S ; Ferensztajn-Rochowiak, E ; König, B ; Kusumi, I ; Laje, G ; Landén, M ; Lavebratt, C ; Leboyer, M ; Leckband, SG ; Maj, M ; Manchia, M ; Martinsson, L ; McCarthy, MJ ; McElroy, S ; Colom, F ; Mitjans, M ; Mondimore, FM ; Monteleone, P ; Nievergelt, CM ; Nöthen, MM ; Novák, T ; O'Donovan, C ; Ozaki, N ; Ösby, U ; Papiol, S ; Pfennig, A ; Pisanu, C ; Potash, JB ; Reif, A ; Reininghaus, E ; Rouleau, GA ; Rybakowski, JK ; Schalling, M ; Schofield, PR ; Schweizer, BW ; Severino, G ; Shekhtman, T ; Shilling, PD ; Shimoda, K ; Simhandl, C ; Slaney, CM ; Squassina, A ; Stamm, T ; Stopkova, P ; Tekola-Ayele, F ; Tortorella, A ; Turecki, G ; Veeh, J ; Vieta, E ; Witt, SH ; Roberts, G ; Zandi, PP ; Alda, M ; Bauer, M ; McMahon, FJ ; Mitchell, PB ; Schulze, TG ; Rietschel, M ; Baune, BT
Link:	Full Text Finder (Volltext)
Zeitschrift:	Translational psychiatry, Jg. 11 (2021-11-29), Heft 1, S. 606
Veröffentlichung:	New York, NY : Nature Pub. Group, 2021
Medientyp:	academicJournal
ISSN:	2158-3188 (electronic)
DOI:	10.1038/s41398-021-01702-2
Schlagwort:	Depression Genetic Predisposition to Disease Humans Lithium therapeutic use Multifactorial Inheritance Risk Factors Bipolar Disorder drug therapy Bipolar Disorder genetics Depressive Disorder, Major drug therapy Depressive Disorder, Major genetics Schizophrenia drug therapy Schizophrenia genetics
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Corporate Authors: Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium Publication Type: Journal Article; Meta-Analysis; Research Support, Non-U.S. Gov't Language: English [Transl Psychiatry] 2021 Nov 29; Vol. 11 (1), pp. 606. <i>Date of Electronic Publication: </i>2021 Nov 29. MeSH Terms: Bipolar Disorder* / drug therapy ; Bipolar Disorder* / genetics ; Depressive Disorder, Major* / drug therapy ; Depressive Disorder, Major* / genetics ; Schizophrenia* / drug therapy ; Schizophrenia* / genetics ; Depression ; Genetic Predisposition to Disease ; Humans ; Lithium / therapeutic use ; Multifactorial Inheritance ; Risk Factors Comments: Erratum in: Transl Psychiatry. 2022 Jul 11;12(1):278. (PMID: 35817769) References: Ferrari AJ, Stockings E, Khoo JP, Erskine HE, Degenhardt L, Vos T, et al. The prevalence and burden of bipolar disorder: findings from the Global Burden of Disease Study 2013. 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(PMID: 3166782910.1111/acps.13122) Substance Nomenclature: 9FN79X2M3F (Lithium) Entry Date(s): Date Created: 20211130 Date Completed: 20220131 Latest Revision: 20220712 Update Code: 20240513 PubMed Central ID: PMC8630000

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Combining schizophrenia and depression polygenic risk scores improves the genetic prediction of lithium response in bipolar disorder patients.