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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
International Consortium on Lithium Genetics (ConLi+Gen), AT. Amare, KO. Schubert, L. Hou, SR. Clark, S. Papiol, U. Heilbronner, F. Degenhardt, F. Tekola-Ayele, YH. Hsu, T. Shekhtman, M. Adli, N. Akula, K. Akiyama, R. Ardau, B. Arias, JM. Aubry,...
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články, randomizované kontrolované studie, Research Support, N.I.H., Extramural, práce podpořená grantem
Perzistentní odkaz
https://www.medvik.cz/link/bmc19035539
Grantová podpora
R21 AR056405
NIAMS NIH HHS - United States
K02 DA021237
NIDA NIH HHS - United States
- MeSH
- bipolární porucha farmakoterapie genetika MeSH
- celogenomová asociační studie * MeSH
- dospělí MeSH
- genetická zátěž MeSH
- genotyp MeSH
- HLA antigeny genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- lithiumkarbonát terapeutické užití MeSH
- multifaktoriální dědičnost genetika MeSH
- schizofrenie (psychologie) MeSH
- schizofrenie farmakoterapie genetika MeSH
- výsledek terapie MeSH
- zánět genetika MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
- Research Support, N.I.H., Extramural MeSH
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 lithium was 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.
Bipolar Center Wiener Neustadt Sigmund Freud University Medical Faculty Vienna Austria
Department of Adult Psychiatry Poznan University of Medical Sciences Poznan Poland
Department of Biomedical Sciences University of Cagliari Cagliari Italy
Department of Clinical Neurosciences Karolinska Institutet Stockholm Sweden
Department of Mental Health Johns Hopkins Bloomberg School of Public Health Baltimore Maryland
Department of Pharmacy Veterans Affairs San Diego Healthcare System San Diego California
Department of Psychiatry 2nd University of Naples Naples Italy
Department of Psychiatry and Behavioral Sciences Johns Hopkins University Baltimore Maryland
Department of Psychiatry and Psychology Mayo Clinic Rochester Minnesota
Department of Psychiatry and Psychotherapy Ludwig Maximilian University of Munich Munich Germany
Department of Psychiatry Dalhousie University Halifax Nova Scotia Canada
Department of Psychiatry Dokkyo University School of Medicine Mibu Tochigi Japan
Department of Psychiatry Hokkaido University Graduate School of Medicine Sapporo Japan
Department of Psychiatry Lindner Center of Hope and University of Cincinnati Mason Ohio
Department of Psychiatry Mood Disorders Unit Geneva University Hospitals Geneva Switzerland
Department of Psychiatry Nagoya University Graduate School of Medicine Nagoya Aichi Japan
Department of Psychiatry University of California San Diego
Department of Psychiatry University of Perugia Perugia Italy
Douglas Mental Health University Institute McGill University Montreal Canada
Laboratory for Molecular Dynamics of Mental Disorders RIKEN Brain Science Institute Saitama Japan
Montreal Neurological Institute and Hospital McGill University Montreal Canada
Mood Disorders Center of Ottawa Ontario Canada
National Institute of Mental Health Klecany Czech Republic
Psychiatric Genetic Unit Poznan University of Medical Sciences Poznan Poland
Service de Psychiatrie Hôpital Charles Perrens Bordeaux France
The Neuromodulation Unit McGill University Health Centre Montreal Canada
Unit of Clinical Pharmacology Hospital University Agency of Cagliari Cagliari Italy
Citace poskytuje Crossref.org
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- $a 10.1001/jamapsychiatry.2017.3433 $2 doi
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- $a International Consortium on Lithium Genetics (ConLi+Gen)
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- $a 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 / $c International Consortium on Lithium Genetics (ConLi+Gen), AT. Amare, KO. Schubert, L. Hou, SR. Clark, S. Papiol, U. Heilbronner, F. Degenhardt, F. Tekola-Ayele, YH. Hsu, T. Shekhtman, M. Adli, N. Akula, K. Akiyama, R. Ardau, B. Arias, JM. Aubry, L. Backlund, AK. Bhattacharjee, F. Bellivier, A. Benabarre, S. Bengesser, JM. Biernacka, A. Birner, C. Brichant-Petitjean, P. Cervantes, HC. Chen, C. Chillotti, S. Cichon, C. Cruceanu, PM. Czerski, N. Dalkner, A. Dayer, M. Del Zompo, JR. DePaulo, B. Étain, P. Falkai, AJ. Forstner, L. Frisen, MA. Frye, JM. Fullerton, S. Gard, JS. Garnham, FS. Goes, M. Grigoroiu-Serbanescu, P. Grof, R. Hashimoto, J. Hauser, S. Herms, P. Hoffmann, A. Hofmann, S. Jamain, E. Jiménez, JP. Kahn, L. Kassem, PH. Kuo, T. Kato, J. Kelsoe, S. Kittel-Schneider, S. Kliwicki, B. König, I. Kusumi, G. Laje, M. Landén, C. Lavebratt, M. Leboyer, SG. Leckband, A. Tortorella, M. Manchia, L. Martinsson, MJ. McCarthy, S. McElroy, F. Colom, M. Mitjans, FM. Mondimore, P. Monteleone, CM. Nievergelt, MM. Nöthen, T. Novák, C. O'Donovan, N. Ozaki, U. Ösby, A. Pfennig, JB. Potash, A. Reif, E. Reininghaus, GA. Rouleau, JK. Rybakowski, M. Schalling, PR. Schofield, BW. Schweizer, G. Severino, PD. Shilling, K. Shimoda, C. Simhandl, CM. Slaney, A. Squassina, T. Stamm, P. Stopkova, M. Maj, G. Turecki, E. Vieta, J. Volkert, S. Witt, A. Wright, PP. Zandi, PB. Mitchell, M. Bauer, M. Alda, M. Rietschel, FJ. McMahon, TG. Schulze, BT. Baune,
- 520 9_
- $a 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 lithium was 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.
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- 700 1_
- $a Schubert, Klaus Oliver $u Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, South Australia, Australia. Northern Adelaide Local Health Network, Mental Health Services, Adelaide, South Australia, Australia.
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
- $a Hsu, Yi-Hsiang $u Hebrew SeniorLife Institute for Aging Research, Harvard Medical School, Boston, Massachusetts. Program for Quantitative Genomics, Harvard School of Public Health, Boston, Massachusetts. Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
- $a Cruceanu, Cristiana $u Douglas Mental Health University Institute, McGill University, Montreal, Canada.
- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
- $a Étain, Bruno $u Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche Scientifique 1144, Université Paris Diderot, Département de Psychiatrie et de Médecine Addictologique, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Saint-Louis-Lariboisière-F. Widal, Paris, France.
- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
- $a Jiménez, Esther $u Bipolar Disorder Program, Institute of Neuroscience, Hospital Clinic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica en Red Salud Mental, Barcelona, Catalonia, Spain.
- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
- $a Schofield, Peter R $u Neuroscience Research Australia, Sydney, New South Wales, Australia. School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia.
- 700 1_
- $a Schweizer, Barbara W $u Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, Maryland.
- 700 1_
- $a Severino, Giovanni $u Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
- 700 1_
- $a Shilling, Paul D $u Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden, and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
- 700 1_
- $a Shimoda, Katzutaka $u Department of Psychiatry, Dokkyo University School of Medicine, Mibu, Tochigi, Japan.
- 700 1_
- $a Simhandl, Christian $u Bipolar Center Wiener Neustadt, Sigmund Freud University, Medical Faculty, Vienna, Austria.
- 700 1_
- $a Slaney, Claire M $u Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada.
- 700 1_
- $a Squassina, Alessio $u Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
- 700 1_
- $a Stamm, Thomas $u Department of Psychiatry and Psychotherapy, Charité-Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany.
- 700 1_
- $a Stopkova, Pavla $u National Institute of Mental Health, Klecany, Czech Republic.
- 700 1_
- $a Maj, Mario $u Department of Psychiatry, Second University of Naples, Naples, Italy.
- 700 1_
- $a Turecki, Gustavo $u Douglas Mental Health University Institute, McGill University, Montreal, Canada.
- 700 1_
- $a Vieta, Eduard $u Bipolar Disorder Program, Institute of Neuroscience, Hospital Clinic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica en Red Salud Mental, Barcelona, Catalonia, Spain.
- 700 1_
- $a Volkert, Julia $u Department of Psychiatry, Psychosomatic Medicine, and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany.
- 700 1_
- $a Witt, Stephanie $u Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
- 700 1_
- $a Wright, Adam $u School of Psychiatry, University of New South Wales, and Black Dog Institute, Sydney, New South Wales, Australia.
- 700 1_
- $a Zandi, Peter P $u Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
- 700 1_
- $a Mitchell, Philip B $u School of Psychiatry, University of New South Wales, and Black Dog Institute, Sydney, New South Wales, Australia.
- 700 1_
- $a Bauer, Michael $u Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Medical Faculty, Technische Universität Dresden, Germany.
- 700 1_
- $a Alda, Martin $u Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada.
- 700 1_
- $a Rietschel, Marcella $u Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
- 700 1_
- $a McMahon, Francis J $u Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland.
- 700 1_
- $a Schulze, Thomas G $u Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland. Institute of Psychiatric Phenomics and Genomics, University Hospital, Ludwig-Maximilian University of Munich, Munich, Germany. Department of Psychiatry and Psychotherapy, University Medical Center, Georg-August University Göttingen, Göttingen, Germany. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, Maryland. Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
- 700 1_
- $a Baune, Bernhard T $u Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
- 773 0_
- $w MED00180928 $t JAMA psychiatry $x 2168-6238 $g Roč. 75, č. 1 (2018), s. 65-74
- 856 41
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