Association of polygenic score for schizophrenia and HLA antigen and inflammation genes with response to lithium in bipolar affective disorder: A genome-wide association study

Amare AT, Schubert KO, Hou L, Clark SR, Papiol S, Heilbronner U, Degenhardt F, Tekola-Ayele F, Hsu YH, Shekhtman T, Adli 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, Brichant-Petitjean C, Cervantes P, Chen HC, Chillotti C, Cichon S, Cruceanu C, Czerski PM, Dalkner N, Dayer A, 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, Herms S, Hoffmann P, Hofmann A, Jamain S, Jiménez E, Kahn JP, Kassem L, Kuo PH, Kato T, Kelsoe J, Kittel-Schneider S, Kliwicki S, König B, Kusumi I, Laje G, Landén M, Lavebratt C, Leboyer M, Leckband SG, Tortorella A, 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, Pfennig A, Potash JB, Reif A, Reininghaus E, Rouleau GA, Rybakowski JK, Schalling M, Schofield PR, Schweizer BW, Severino G, Shilling PD, Shimoda K, Simhandl C, Slaney CM, Squassina A, Stamm T, Stopkova P, Maj M, Turecki G, Vieta E, Volkert J, Witt S, Wright A, Zandi PP, Mitchell PB, Bauer M, Alda M, Rietschel M, McMahon FJ, Schulze TG, Baune BT (2018)

Publication Type: Journal article

Publication year: 2018

Journal

Book Volume: 75

Pages Range: 65-74

Journal Issue: 1

DOI: 10.1001/jamapsychiatry.2017.3433

Abstract

IMPORTANCE Lithium is a first-line mood stabilizer for the treatment of bipolar affective disorder (BPAD). However, the efficacy of lithium varies widely, with a nonresponse rate of up to 30%. Biological response markers are lacking. Genetic factors are thought to mediate treatment response to lithium, and there is a previously reported genetic overlap between BPAD and schizophrenia (SCZ). OBJECTIVES To test whether a polygenic score for SCZ is associated with treatment response to lithium in BPAD and to explore the potential molecular underpinnings of this association. DESIGN, SETTING, AND PARTICIPANTS A total of 2586 patients with BPAD who had undergone lithium treatment were genotyped and assessed for long-term response to treatment between 2008 and 2013.Weighted SCZ polygenic scores were computed at different P value thresholds using summary statistics from an international multicenter genome-wide association study (GWAS) of 36 989 individuals with SCZ and genotype data from patients with BPAD from the Consortium on Lithium Genetics. For functional exploration, a cross-trait meta-GWAS and pathway analysis was performed, combining GWAS summary statistics on SCZ and response to treatment with lithium. Data analysis was performed from September 2016 to February 2017. MAIN OUTCOMES AND MEASURES Treatment response to lithiumwas defined on both the categorical and continuous scales using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. The effect measures include odds ratios and the proportion of variance explained. RESULTS Of the 2586 patients in the study (mean [SD] age, 47.2 [13.9] years), 1478 were women and 1108 were men. The polygenic score for SCZ was inversely associated with lithium treatment response in the categorical outcome, at a threshold P < 5 ? 10-2. Patients with BPAD who had a low polygenic load for SCZ responded better to lithium, with odds ratios for lithium response ranging from 3.46 (95%CI, 1.42-8.41) at the first decile to 2.03 (95%CI, 0.86-4.81) at the ninth decile, compared with the patients in the 10th decile of SCZ risk. In the cross-trait meta-GWAS, 15 genetic loci that may have overlapping effects on lithium treatment response and susceptibility to SCZ were identified. Functional pathway and network analysis of these loci point to the HLA antigen complex and inflammatory cytokines. CONCLUSIONS AND RELEVANCE This study provides evidence for a negative association between high genetic loading for SCZ and poor response to lithium in patients with BPAD. These results suggest the potential for translational research aimed at personalized prescribing of lithium.

Involved external institutions

Universitätsklinikum Frankfurt am Main (KGU) Germany (DE) Karolinska Institute Sweden (SE) Neuroscience Research Australia NeuRA Australia (AU) Johns Hopkins University (JHU) United States (USA) (US) National Taiwan University (NTU) Taiwan (TW) RIKEN Center for Brain Science (CBS) Japan (JP) Dokkyo Medical University Japan (JP) Università degli Studi di Cagliari Italy (IT) Universitat de Barcelona (UB) / University of Barcelona Spain (ES) Geneva University Hospitals / Hôpitaux universitaires de Genève (HUG) Switzerland (CH) University of California, San Diego (UC San Diego, UCSD) United States (USA) (US) Ruprecht-Karls-Universität Heidelberg Germany (DE) University of New South Wales (UNSW) Australia (AU) Universitätsklinikum Carl Gustav Carus Dresden Germany (DE) Université Paris Cité France (FR) Medizinische Universität Graz Austria (AT) Dalhousie University Canada (CA) Mayo Clinic United States (USA) (US) National Institute of Mental Health Information Resource Center United States (USA) (US) University of Adelaide Australia (AU) McGill University Health Centre (MUHC) / Centre universitaire de santé McGill Canada (CA) National Taiwan University Hospital (NTUH) / 國立台灣大學醫學院附設醫院 Taiwan (TW) Rheinische Friedrich-Wilhelms-Universität Bonn Germany (DE) National Institute for Health and Medical Research / Institut national de la santé et de la recherche médicale (INSERM) France (FR) Université de Lorraine France (FR) Poznan University of Medical Sciences / Uniwersytet Medyczny im. Karola Marcinkowskiego w Poznaniu Poland (PL) Sahlgrenska University Hospital / Sahlgrenska Universitetssjukhuset Sweden (SE) Nagoya University / 名古屋大学 Japan (JP) Karolinska University Hospital / Karolinska Universitetssjukhuset Sweden (SE) Montreal Neurological Institute and Hospital (MNI, The Neuro) Canada (CA) Centre Hospitalier Charles Perrens (CHCP) France (FR) University of Cincinnati United States (USA) (US) Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM) Spain (ES) Università degli Studi di Salerno Italy (IT) Paris-Est Créteil University / Université Paris-Est Créteil Val-de-Marne (UPEC) / Université Paris XII-Val-de-Marne / University Paris 12 Marne la Vallée France (FR) VA San Diego Healthcare System United States (USA) (US) Università degli Studi di Perugia Italy (IT) Klinikum der Universität München (LMU Klinikum) Germany (DE) US National Institutes of Health (NIH) United States (USA) (US) Harvard University United States (USA) (US) Charité - Universitätsmedizin Berlin Germany (DE) Sigmund-Freud-Privatuniversität Wien (SFU) / Sigmund Freud University Austria (AT) National Institute of Mental Health (NIMH) / Národní ústav duševního zdraví (NUDZ) Czech Republic (CZ) Università degli studi della Campania Luigi Vanvitelli Italy (IT) Douglas Mental Health University Institute Canada (CA) Mood Disorders Ottawa Canada (CA) Osaka University / 大阪大学 Japan (JP)

How to cite

APA:

Amare, A.T., Schubert, K.O., Hou, L., Clark, S.R., Papiol, S., Heilbronner, U.,... Baune, B.T. (2018). Association of polygenic score for schizophrenia and HLA antigen and inflammation genes with response to lithium in bipolar affective disorder: A genome-wide association study. JAMA Psychiatry, 75(1), 65-74. https://doi.org/10.1001/jamapsychiatry.2017.3433

MLA:

Amare, Azmeraw T., et al. "Association of polygenic score for schizophrenia and HLA antigen and inflammation genes with response to lithium in bipolar affective disorder: A genome-wide association study." JAMA Psychiatry 75.1 (2018): 65-74.

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