Association of Polygenic Score for Schizophrenia and HLA Antigen and Inflammation Genes With Response to Lithium in Bipolar Affective Disorder
Year: 2017
Type: article
Study design: Observational Study
Abstract: ABSTRACT Importance Lithium is a first-line mood stabilizer for the maintenance treatment of Bipolar Disorder (BPD). However, the efficacy of lithium varies widely, with a non-response rate of up to 30%. Biological response markers and predictors are lacking. Objective Genetic factors are thought to mediate lithium treatment response, and the previously reported genetic overlap between BPD and schizophrenia (SCZ) led us to test whether a polygenic score (PGS) for SCZ could predict lithium treatment response in BPD. Further, we explored the potential molecular underpinnings of this association. Design Weighted SCZ PGSs were computed at ten p-value thresholds (P T ) using summary statistics from a genome-wide association study (GWAS) of 36,989 SCZ cases, and genotype data for BPD patients from the Consortium on Lithium Genetics (ConLi + Gen). For functional exploration, we performed a cross-trait meta-GWAS and pathway analysis, combining GWAS summary statistics on SCZ and lithium treatment response. Setting International multicenter GWAS. Participants Patients with BPD who had undergone lithium treatment were genotyped and retrospectively assessed for long-term treatment response (n=2,586). Main outcome measures Clinical treatment response to lithium was defined on both the categorical and continuous scales using the ALDA score. The effect measures include odds ratios (ORs) and the proportion of variance explained (R 2 ), and a significant association was determined at p<0.05. Results The PGS for SCZ was inversely associated with lithium treatment response in the categorical outcome (p=8×10 −5 ), at P T <5×10 −2 . Patients with BPD who had low polygenic load for SCZ responded better to lithium, with ORs for lithium response ranging from 3.46 [95%CI: 1.42-8.41 at 1 st decile] to 2.03 [95%CI: 0.86-4.81 at the 9th decile], compared to the patients in the 10 th 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 complex and inflammatory cytokines (TNFα, IL-4, IFNγ) as molecular contributors to lithium treatment response in BPD. Conclusions and Relevance The study provides, for the first-time, evidence for a negative association between high genetic loading for SCZ and poor response to lithium in patients with BPD. These results suggest the potential for translational research aimed at personalized prescribing of lithium. Key Points Question Does a polygenic score for Schizophrenia (SCZ) predict response to lithium in patients with Bipolar Disorder (BPD)? What are the molecular drivers of the association between SCZ and lithium treatment response? Findings We found an inverse association between genetic loading for SCZ risk variants and response to lithium in patients with BPD. Genetic variants in the HLA region on chromosome 6, the antigen presentation pathway and markers of inflammation (TNFα, IL-4, IFNγ) point to molecular underpinnings of lithium treatment response in BPD. Meaning In patients with BPD, an assessment of a polygenic load for SCZ risk variants may assist in conjunction with clinical data to predict whether they would respond to lithium treatment.
Source: JAMA Psychiatry
Authors: Azmeraw T. Amare, Klaus Oliver Schubert, Liping Hou, Scott R. Clark, Sergi Papiol, Urs Heilbronner, Franziska Degenhardt, Fasil Tekola-Ayele, Yi-Hsiang Hsu, Tatyana Shekhtman, Mazda Adli, 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, Clara Brichant-Petitjean, Pablo Cervantes, Hsi-Chung Chen, Caterina Chillotti, Sven Cichon, Cristiana Cruceanu, Piotr M. Czerski, Nina Dalkner, Alexandre Dayer, 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, Stefan Herms, Per Hoffmann, Andrea Hofmann, Stephane Jamain, Esther Jiménez, Jean-Pierre Kahn, Layla Kassem, Po-Hsiu Kuo, Tadafumi Kato, John Kelsoe, Sarah Kittel-Schneider, Sebastian Kliwicki, Barbara König, Ichiro Kusumi, Gonzalo Laje, Mikael Landén, Catharina Lavebratt, Marion Leboyer, Susan G. Leckband, Alfonso Tortorella, 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, Andrea Pfennig, James B. Potash, Andreas Reif, Eva Reininghaus, Guy A. Rouleau, Janusz K. Rybakowski, Martin Schalling, Peter R. Schofield, Barbara W. Schweizer, Giovanni Severino, Paul D. Shilling, Katzutaka Shimoda, Christian Simhandl, Claire M. Slaney, Alessio Squassina, Thomas Stamm, Pavla Stopkova, Mario Maj, Gustavo Turecki, Eduard Vieta, Julia Volkert, Stephanie Witt, Adam Wright, Peter P. Zandi, Philip B. Mitchell, Michael Bauer, Martin Alda, Marcella Rietschel, Francis J. McMahon, Thomas G. Schulze, Bernhard T. Baune
Institutions: The University of Adelaide, National Institutes of Health, National Institute of Mental Health, Institut für Psychiatrische Phänomik und Genomik, Ludwig-Maximilians-Universität München, Universitätsmedizin Göttingen, University of Göttingen, University of Bonn, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Broad Institute, Harvard University, Hebrew SeniorLife, Massachusetts Institute of Technology, University of California San Diego, Charité – Universitätsmedizin Berlin, Dokkyo Medical University, Azienda Ospedaliero-Universitaria Cagliari, Centro de Investigación Biomédica en Red de Salud Mental, Institut de Biomedicina de la Universitat de Barcelona, Universitat de Barcelona, University Hospital of Geneva, Karolinska University Hospital, Karolinska Institutet, Inserm, Assistance Publique – Hôpitaux de Paris, Université Paris Diderot, Optimisation Thérapeutique en Neuropsychopharmacologie, Medical University of Graz, Mayo Clinic, McGill University Health Centre, National Taiwan University Hospital, University Hospital of Basel, Douglas Mental Health University Institute, McGill University, Poznan University of Medical Sciences, University of Cagliari, Johns Hopkins University, University of Basel, UNSW Sydney, Neuroscience Research Australia, Centre Hospitalier Charles Perrens, Dalhousie University, Spitalul Clinic de Psihiatrie Alexandru Obregia, Molecular Research Center for Children's Mental Development, The University of Osaka, Université de Lorraine, National Taiwan University, RIKEN, University Hospital Frankfurt, Hokkaido University, University of Gothenburg, Université Paris-Est Créteil, Hôpitaux Universitaires Henri-Mondor, Hôpital Albert-Chenevier, VA San Diego Healthcare System, University of Perugia, Lindner Center of HOPE, University of Cincinnati, Municipal Institute for Medical Research, Instituto de Salud Carlos III, Max Planck Institute of Experimental Medicine, University of Salerno, University of Campania "Luigi Vanvitelli", National Institute of Mental Health, Nagoya University, University Hospital Carl Gustav Carus, Technische Universität Dresden, Montreal Neurological Institute and Hospital, Dokkyo University, Sigmund Freud Privatuniversität Wien, Heidelberg University, Central Institute of Mental Health, Medizinische Fakultät Mannheim, Black Dog Institute
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funders: U.S. Department of Veterans Affairs, Massachusetts Institute of Technology, Università degli Studi di Napoli Federico II, Johns Hopkins University, University of Cincinnati, Universität Basel, McGill University, Université de Lorraine, Neuroscience Research Australia, Università degli Studi di Cagliari, Broad Institute, McGill University Health Centre, Centres de Recerca de Catalunya, Deutsche Forschungsgemeinschaft, Universität Heidelberg, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, University of New South Wales, University of Adelaide, Grantová Agentura České Republiky, Bundesministerium für Bildung und Forschung, Generalitat de Catalunya, Dokkyo Medical University, Technische Universität Dresden, Dalhousie University, Karolinska Institutet, Seconda Università degli Studi di Napoli, Stockholms Läns Landsting, Vetenskapsrådet, Université Paris Diderot, National Taiwan University Hospital, Universitat de Barcelona, Hokkaido University, Hôpitaux Universitaires de Genève, National Taiwan University, Centro de Investigación Biomédica en Red de Salud Mental, Università degli Studi di Salerno, Rheinische Friedrich-Wilhelms-Universität Bonn, Karl-Franzens-Universität Graz, Assistance publique-Hôpitaux de Paris, Medizinische Universität Graz, Uniwersytet Medyczny im. Karola Marcinkowskiego w Poznaniu, Università degli Studi di Perugia, National Institutes of Health, University of California, San Diego, Johns Hopkins Bloomberg School of Public Health, Veterans Affairs San Diego Healthcare System, Montreal Neurological Institute and Hospital, Canadian Institutes of Health Research, National Health and Medical Research Council, Japan Society for the Promotion of Science, Instituto de Salud Carlos III, Sahlgrenska Akademin, RIKEN, National Institute of Mental Health, National Institute on Drug Abuse, National Cancer Institute, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institute of Child Health and Human Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, RIKEN Brain Science Institute
Awards: G1039077240, G1154649974, G1255536505, Mapping genes that contribute to bipolar disorder, G417657078, G4304029336, G4516721171, G6125999700, G6216796152, Sorbonne Universités à Paris pour l'Enseignement et la Recherche, G6663863164, G6733821374, Human Genetics of Addiction: A Study of Common and Specific Factors, G704728439, Osteocalcin and Metabolic Risk Factors. The Framingham Study, Association of the 40 candidate gene variants with Cognitive Function in Japanese Subjects, G8267165792, G829097553, G83893951, G8400043944, Depressive and bipolar disorders: Causes, presentation and treatment innovations, G8600254050, Mega-analysis of brain structure vulnerability of schizophrenia
OpenAlex ID: W2768987398