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

Title:	Combining schizophrenia and depression polygenic risk scores improves the genetic prediction of lithium response in bipolar disorder patients
Authors:	Schubert, Klaus Oliver; Thalamuthu, Anbupalam; Amare, Azmeraw T.; Frank, Joseph; Streit, Fabian; Adl, Mazda; Akula, Nirmala; Akiyama, Kazufumi; Ardau, Raffaella; Arias, Bárbara; Aubry, Jean-Michel; Backlund, Lena; Bhattacharjee, Abesh Kumar; Bellivier, Frank; Benabarre, Antonio; Bengesser, Susanne; Biernacka, Joanna M.; Birner, Armin; Marie-Claire, Cynthia; Cearns, Micah; Cervantes, Pablo; Chen, Hsi-Chung; Chillotti, Caterina; Cichon, Sven; Clark, Scott R.; Cruceanu, Cristiana; Czerski, Piotr M.; Dalkner, Nina; Dayer, Alexandre; Degenhardt, Franziska; Del Zompo, Maria; DePaulo, J. Raymond; Étain, Bruno; Falkai, Peter; Forstner, Andreas J.; Frisen, Louise; Frye, Mark A.; Fullerton, Janice M.; Gard, Sébastien; Garnham, Julie S.; Goes, Fernando S.; Grigoroiu-Serbanescu, Maria; Grof, Paul; Hashimoto, Ryota; Hauser, Joanna; Heilbronner, Urs; Herms, Stefan; Hoffmann, Per; Hou, Liping; Hsu, Yi-Hsiang; Jamain, Stephane; Jiménez, Esther; Kahn, Jean-Pierre; Kassem, Layla; Kuo, Po-Hsiu; Kato, Tadafumi; Kelsoe, John; Kittel-Schneider, Sarah; Ferensztajn-Rochowiak, Ewa; König, Barbara; Kusumi, Ichiro; Laje, Gonzalo; Landén, Mikael; Lavebratt, Catharina; Leboyer, Marion; Leckband, Susan G.; Maj, Mario; Manchia, Mirko; Martinsson, Lina; McCarthy, Michael J.; McElroy, Susan; Colom, Francesc; Mitjans, Marina; Mondimore, Francis M.; Monteleone, Palmiero; Nievergelt, Caroline M.; Nöthen, Markus M.; Novák, Tomas; O’Donovan, Claire; Ozaki, Norio; Ösby, Urban; Papiol, Sergi; Pfennig, Andrea; Pisanu, Claudia; Potash, James B.; Reif, Andreas; Reininghaus, Eva; Rouleau, Guy A.; Rybakowski, Janusz K.; Schalling, Martin; Schofield, Peter R.; Schweizer, Barbara W.; Severino, Giovanni; Shekhtman, Tatyana; Shilling, Paul D.; Shimoda, Katzutaka; Simhandl, Christian; Slaney, Claire M.; Squassina, Alessio; Stamm, Thomas; Stopkova, Pavla; Tekola-Ayele, Fasil; Tortorella, Alfonso; Turecki, Gustavo; Veeh, Julia; Vieta, Eduard; Witt, Stephanie H.; Roberts, Gloria; Zandi, Peter P.; Alda, Martin; Bauer, Michael; McMahon, Francis J.; Mitchell, Philip B.; Schulze, Thomas G.; Rietschel, Marcella; Baune, Bernhard T.; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium; Northern Adelaide Local Health Network, Mental Health Services, Adelaide, Australia; Centre for Healthy Brain Ageing (CHeBA), School of Psychiatry, University of New South Wales, Sydney, Australia; Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, Australia; Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; Department of Psychiatry and Psychotherapy, Charité—Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany; Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health & Human Services, Bethesda, USA; Department of Biological Psychiatry and Neuroscience, Dokkyo Medical University School of Medicine, Mibu, Japan; Unit of Clinical Pharmacology, Hospital University Agency of Cagliari, Cagliari, Italy; Unitat de Zoologia i Antropologia Biològica (Dpt. Biologia Evolutiva, Ecologia i Ciències Ambientals), Facultat de Biologia and Institut de Biomedicina (IBUB), University of Barcelona, CIBERSAM, Barcelona, Spain; Department of Psychiatry, Mood Disorders Unit, HUG—Geneva University Hospitals, Geneva, Switzerland; Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden, and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden; Department of Psychiatry, University of California San Diego, San Diego, USA; INSERM UMR-S 1144, Université Paris Diderot, Département de Psychiatrie et de Médecine Addictologique, AP-HP, Groupe Hospitalier Saint-Louis-Lariboisière-F.Widal, Paris, France; Bipolar Disorder Program, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Spain; Department of Psychiatry and Psychotherapeutic Medicine, Research Unit for bipolar affective disorder, Medical University of Graz, Graz, Austria; Department of Psychiatry and Psychology, Mayo Clinic, Rochester, USA; The Neuromodulation Unit, McGill University Health Centre, Montreal, Canada; Department of Psychiatry & Center of Sleep Disorders, National Taiwan University Hospital, Taipei, Taiwan; Institute of Human Genetics, University of Bonn and Department of Genomics, Life & Brain Center, Bonn, Germany; Douglas Mental Health University Institute, McGill University, Montreal, Canada; Psychiatric Genetic Unit, Poznan University of Medical Sciences, Poznan, Poland; Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, USA; Department of Psychiatry and Psychotherapy, Ludwig-Maximilian-University Munich, Munich, Germany; Department of Psychiatry (UPK), University of Basel, Basel, Switzerland; School of Medical Sciences, University of New South Wales, Sydney, Australia; Service de psychiatrie, Hôpital Charles Perrens, Bordeaux, France; Department of Psychiatry, Dalhousie University, Halifax, Canada; Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Bucharest, Romania; Mood Disorders Center of Ottawa, Ottawa, Canada; Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, Japan; Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Munich, Germany; Program for Quantitative Genomics, Harvard School of Public Health, Boston, USA; Univ Paris Est Créteil, INSERM, IMRB, Translational Neuropsychiatry, Fondation FondaMental, Créteil, France; Service de Psychiatrie et Psychologie Clinique, Centre Psychothérapique de Nancy—Université de Lorraine, Nancy, France; Department of Public Health & Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan; Department of Psychiatry & Behavioral Science, Juntendo University, Graduate School of Medicine, Tokyo, Japan; Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany; Department of Adult Psychiatry, Poznan University of Medical Sciences, Poznan, Poland; Department of Psychiatry and Psychotherapeutic Medicine, Landesklinikum Neunkirchen, Neunkirchen, Austria; Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Inserm U955, Translational Neuro-Psychiatry laboratory, Université Paris Est Créteil (UPEC), AP-HP, Department of Psychiatry and Addictology of Mondor University Hospital, AP-HP, Fondation FondaMental, Créteil, France; Office of Mental Health, VA San Diego Healthcare System, San Diego, USA; Department of Psychiatry, University of Campania “Luigi Vanvitelli”, Naples, Italy; Department of Pharmacology, Dalhousie University, Halifax, Canada; Department of Clinical Neurosciences, Karolinska Institutet, Stockholm, Sweden; Department of Psychiatry, VA San Diego Healthcare System, San Diego, USA; Department of Psychiatry, Lindner Center of Hope / University of Cincinnati, Mason, USA; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain; Centro de Investigación Biomédica en Salud Mental (CIBERSAM), Madrid, Spain; Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Salerno, Italy; National Institute of Mental Health, Klecany, Czech Republic; Department of Psychiatry & Department of Child and Adolescent Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden; Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Medical Faculty, Technische Universität Dresden, Dresden, Germany; Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada; Department of Psychiatry, Dokkyo Medical University School of Medicine, Mibu, Japan; Bipolar Center Wiener Neustadt, Sigmund Freud University, Medical Faculty, Vienna, Austria; Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, USA; Department of Psychiatry, University of Perugia, Perugia, Italy; School of Psychiatry, University of New South Wales, Sydney, Australia; Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, USA; Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August University Göttingen, Göttingen, Germany; The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Australia
Contributors:	Schubert, Klaus Oliver; Thalamuthu, Anbupalam; Amare, Azmeraw T.; Frank, Joseph; Streit, Fabian; Adl, Mazda; Akula, Nirmala; Akiyama, Kazufumi; Ardau, Raffaella; Arias, Bárbara; Aubry, Jean-Michel; Backlund, Lena; Bhattacharjee, Abesh Kumar; Bellivier, Frank; Benabarre, Antonio; Bengesser, Susanne; Biernacka, Joanna M.; Birner, Armin; Marie-Claire, Cynthia; Cearns, Micah; Cervantes, Pablo; Chen, Hsi-Chung; Chillotti, Caterina; Cichon, Sven; Clark, Scott R.; Cruceanu, Cristiana; Czerski, Piotr M.; Dalkner, Nina; Dayer, Alexandre; Degenhardt, Franziska; Del Zompo, Maria; DePaulo, J. Raymond; Étain, Bruno; Falkai, Peter; Forstner, Andreas J.; Frisen, Louise; Frye, Mark A.; Fullerton, Janice M.; Gard, Sébastien; Garnham, Julie S.; Goes, Fernando S.; Grigoroiu-Serbanescu, Maria; Grof, Paul; Hashimoto, Ryota; Hauser, Joanna; Heilbronner, Urs; Herms, Stefan; Hoffmann, Per; Hou, Liping; Hsu, Yi-Hsiang; Jamain, Stephane; Jiménez, Esther; Kahn, Jean-Pierre; Kassem, Layla; Kuo, Po-Hsiu; Kato, Tadafumi; Kelsoe, John; Kittel-Schneider, Sarah; Ferensztajn-Rochowiak, Ewa; König, Barbara; Kusumi, Ichiro; Laje, Gonzalo; Landén, Mikael; Lavebratt, Catharina; Leboyer, Marion; Leckband, Susan G.; Maj, Mario; Manchia, Mirko; Martinsson, Lina; McCarthy, Michael J.; McElroy, Susan; Colom, Francesc; Mitjans, Marina; Mondimore, Francis M.; Monteleone, Palmiero; Nievergelt, Caroline M.; Nöthen, Markus M.; Novák, Tomas; O’Donovan, Claire; Ozaki, Norio; Ösby, Urban; Papiol, Sergi; Pfennig, Andrea; Pisanu, Claudia; Potash, James B.; Reif, Andreas; Reininghaus, Eva; Rouleau, Guy A.; Rybakowski, Janusz K.; Schalling, Martin; Schofield, Peter R.; Schweizer, Barbara W.; Severino, Giovanni; Shekhtman, Tatyana; Shilling, Paul D.; Shimoda, Katzutaka; Simhandl, Christian; Slaney, Claire M.; Squassina, Alessio; Stamm, Thomas
Publication Year:	2021
Collection:	Georg-August-Universität Göttingen: GoeScholar
Description:	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. ; Brain and Behavior Research Foundation (Brain & Behavior Research Foundation) https://doi.org/10.13039/100000874
Document Type:	article in journal/newspaper
Language:	English
Relation:	1702
DOI:	10.1038/s41398-021-01702-2
Availability:	https://resolver.sub.uni-goettingen.de/purl?gro-2/123424; https://doi.org/10.1038/s41398-021-01702-2
Rights:	info:eu-repo/semantics/openAccess ; CC BY 4.0 ; https://creativecommons.org/licenses/by/4.0/
Accession Number:	edsbas.EF5244C
Database:	BASE