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

doi:10.1001/jamapsychiatry.2017.3433

Randomized Controlled Trial

. 2018 Jan 1;75(1):65-74.

doi: 10.1001/jamapsychiatry.2017.3433.

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); Azmeraw T Amare¹, Klaus Oliver Schubert^{1

2}, Liping Hou³, Scott R Clark¹, Sergi Papiol^{4

5}, Urs Heilbronner^{4

6}, Franziska Degenhardt⁷, Fasil Tekola-Ayele⁸, Yi-Hsiang Hsu^{9

10

11}, Tatyana Shekhtman¹², Mazda Adli¹³, Nirmala Akula³, Kazufumi Akiyama¹⁴, Raffaella Ardau¹⁵, Bárbara Arias¹⁶, Jean-Michel Aubry¹⁷, Lena Backlund¹⁸, Abesh Kumar Bhattacharjee¹², Frank Bellivier¹⁹, Antonio Benabarre²⁰, Susanne Bengesser²¹, Joanna M Biernacka^{22

23}, Armin Birner²¹, Clara Brichant-Petitjean¹⁹, Pablo Cervantes²⁴, Hsi-Chung Chen²⁵, Caterina Chillotti¹⁵, Sven Cichon^{7

26}, Cristiana Cruceanu²⁷, Piotr M Czerski²⁸, Nina Dalkner²¹, Alexandre Dayer¹⁷, Maria Del Zompo²⁹, J Raymond DePaulo³⁰, Bruno Étain¹⁹, Peter Falkai⁵, Andreas J Forstner^{7

26

31}, Louise Frisen¹⁸, Mark A Frye²³, Janice M Fullerton^{32

33}, Sébastien Gard³⁴, Julie S Garnham³⁵, Fernando S Goes³⁰, Maria Grigoroiu-Serbanescu³⁶, Paul Grof³⁷, Ryota Hashimoto^{38

39}, Joanna Hauser²⁸, Stefan Herms^{7

26}, Per Hoffmann^{7

26}, Andrea Hofmann⁷, Stephane Jamain⁴⁰, Esther Jiménez²⁰, Jean-Pierre Kahn⁴¹, Layla Kassem³, Po-Hsiu Kuo⁴², Tadafumi Kato⁴³, John Kelsoe¹², Sarah Kittel-Schneider⁴⁴, Sebastian Kliwicki⁴⁵, Barbara König⁴⁶, Ichiro Kusumi⁴⁷, Gonzalo Laje³, Mikael Landén^{48

49}, Catharina Lavebratt¹⁸, Marion Leboyer⁵⁰, Susan G Leckband⁵¹, Alfonso Tortorella⁵², Mirko Manchia^{53

54}, Lina Martinsson⁵⁵, Michael J McCarthy^{12

56}, Susan McElroy⁵⁷, Francesc Colom^{20

58}, Marina Mitjans^{59

60}, Francis M Mondimore³⁰, Palmiero Monteleone^{61

62}, Caroline M Nievergelt¹², Markus M Nöthen⁷, Tomas Novák⁶³, Claire O'Donovan³⁵, Norio Ozaki⁶⁴, Urban Ösby⁶⁵, Andrea Pfennig⁶⁶, James B Potash³⁰, Andreas Reif⁴³, Eva Reininghaus²¹, Guy A Rouleau⁶⁷, Janusz K Rybakowski⁴⁴, Martin Schalling¹⁸, Peter R Schofield^{32

33}, Barbara W Schweizer³⁰, Giovanni Severino²⁹, Paul D Shilling¹⁸, Katzutaka Shimoda⁶⁸, Christian Simhandl⁶⁹, Claire M Slaney³⁵, Alessio Squassina²⁹, Thomas Stamm¹³, Pavla Stopkova⁶³, Mario Maj⁶², Gustavo Turecki²⁷, Eduard Vieta²⁰, Julia Volkert⁴⁴, Stephanie Witt⁷⁰, Adam Wright⁷¹, Peter P Zandi⁷², Philip B Mitchell⁷¹, Michael Bauer⁶⁶, Martin Alda³⁵, Marcella Rietschel⁷⁰, Francis J McMahon³, Thomas G Schulze^{3

4

6

30

70}, Bernhard T Baune¹

Affiliations

¹ Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
² Northern Adelaide Local Health Network, Mental Health Services, Adelaide, South Australia, Australia.
³ Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland.
⁴ Institute of Psychiatric Phenomics and Genomics, University Hospital, Ludwig-Maximilian University of Munich, Munich, Germany.
⁵ Department of Psychiatry and Psychotherapy, Ludwig-Maximilian University of Munich, Munich, Germany.
⁶ Department of Psychiatry and Psychotherapy, University Medical Center, Georg-August University Göttingen, Göttingen, Germany.
⁷ Institute of Human Genetics and Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
⁸ Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.
⁹ Hebrew SeniorLife Institute for Aging Research, Harvard Medical School, Boston, Massachusetts.
¹⁰ Program for Quantitative Genomics, Harvard School of Public Health, Boston, Massachusetts.
¹¹ Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
¹² Department of Psychiatry, University of California San Diego.
¹³ Department of Psychiatry and Psychotherapy, Charité-Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany.
¹⁴ Department of Biological Psychiatry and Neuroscience, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan.
¹⁵ Unit of Clinical Pharmacology, Hospital University Agency of Cagliari, Cagliari, Italy.
¹⁶ Unitat de Zoologia i Antropologia Biològica (Dpt Biologia Evolutiva, Ecologia i Ciències Ambientals), Facultat de Biologia and Institut de Biomedicina, University of Barcelona, Centro de Investigación Biomédica en Red de Salud Mental, Barcelona, Spain.
¹⁷ Department of Psychiatry, Mood Disorders Unit, Geneva University Hospitals, Geneva, Switzerland.
¹⁸ Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden, and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
¹⁹ 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.
²⁰ 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.
²¹ Department of Psychiatry and Psychotherapeutic Medicine, Research Unit for Bipolar Affective Disorder, Medical University of Graz, Graz, Austria.
²² Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.
²³ Department of Psychiatry and Psychology, Mayo Clinic, Rochester, Minnesota.
²⁴ The Neuromodulation Unit, McGill University Health Centre, Montreal, Canada.
²⁵ Department of Psychiatry and Center of Sleep Disorders, National Taiwan University Hospital, Taipei, Taiwan.
²⁶ Human Genomics Research Group, Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
²⁷ Douglas Mental Health University Institute, McGill University, Montreal, Canada.
²⁸ Psychiatric Genetic Unit, Poznan University of Medical Sciences, Poznan, Poland.
²⁹ Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
³⁰ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, Maryland.
³¹ Department of Psychiatry, University of Basel, Basel, Switzerland.
³² Neuroscience Research Australia, Sydney, New South Wales, Australia.
³³ School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia.
³⁴ Service de Psychiatrie, Hôpital Charles Perrens, Bordeaux, France.
³⁵ Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada.
³⁶ Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Bucharest, Romania.
³⁷ Mood Disorders Center of Ottawa, Ontario, Canada.
³⁸ Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Osaka, Japan.
³⁹ Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, Japan.
⁴⁰ Institut National de la Santé et de la Recherche Médicale Unité 955, Psychiatrie Translationnelle, Créteil, France.
⁴¹ Service de Psychiatrie et Psychologie Clinique, Centre Psychothérapique de Nancy, Université de Lorraine, Nancy, France.
⁴² Department of Public Health and Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
⁴³ Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Saitama, Japan.
⁴⁴ Department of Psychiatry, Psychosomatic Medicine, and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany.
⁴⁵ Department of Adult Psychiatry, Poznan University of Medical Sciences, Poznan, Poland.
⁴⁶ Department of Psychiatry and Psychotherapeutic Medicine, Landesklinikum Neunkirchen, Neunkirchen, Austria.
⁴⁷ Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
⁴⁸ Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the Gothenburg University, Gothenburg, Sweden.
⁴⁹ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁵⁰ Inserm U955, Translational Psychiatry Laboratory, Université Paris-Est-Créteil, Department of Psychiatry and Addictology of Mondor University Hospital, Assistance Publique-Hôpitaux de Paris, Hôpital Albert Chenevier-Henri Mondor, Pôle de Psychiatrie, Créteil, France.
⁵¹ Department of Pharmacy, Veterans Affairs San Diego Healthcare System, San Diego, California.
⁵² Department of Psychiatry, University of Perugia, Perugia, Italy.
⁵³ Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy.
⁵⁴ Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
⁵⁵ Department of Clinical Neurosciences, Karolinska Institutet, Stockholm, Sweden.
⁵⁶ Department of Psychiatry, Veterans Affairs San Diego Healthcare System, San Diego, California.
⁵⁷ Department of Psychiatry, Lindner Center of Hope and University of Cincinnati, Mason, Ohio.
⁵⁸ Mental Health Research Group, IMIM-Hospital del Mar, Barcelona, Catalonia, Spain.
⁵⁹ Centro de Investigación Biomédica en Red de Salud Mental, Instituto de Salud Carlos III, Madrid, Spain.
⁶⁰ Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
⁶¹ Neurosciences Section, Department of Medicine and Surgery, University of Salerno, Salerno, Italy.
⁶² Department of Psychiatry, Second University of Naples, Naples, Italy.
⁶³ National Institute of Mental Health, Klecany, Czech Republic.
⁶⁴ Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
⁶⁵ Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
⁶⁶ Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Medical Faculty, Technische Universität Dresden, Germany.
⁶⁷ Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada.
⁶⁸ Department of Psychiatry, Dokkyo University School of Medicine, Mibu, Tochigi, Japan.
⁶⁹ Bipolar Center Wiener Neustadt, Sigmund Freud University, Medical Faculty, Vienna, Austria.
⁷⁰ Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
⁷¹ School of Psychiatry, University of New South Wales, and Black Dog Institute, Sydney, New South Wales, Australia.
⁷² Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.

PMID: 29121268
PMCID: PMC5833535
DOI: 10.1001/jamapsychiatry.2017.3433

Randomized Controlled Trial

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) et al. JAMA Psychiatry. 2018.

. 2018 Jan 1;75(1):65-74.

doi: 10.1001/jamapsychiatry.2017.3433.

Authors

Affiliations

¹ Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
² Northern Adelaide Local Health Network, Mental Health Services, Adelaide, South Australia, Australia.
³ Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland.
⁴ Institute of Psychiatric Phenomics and Genomics, University Hospital, Ludwig-Maximilian University of Munich, Munich, Germany.
⁵ Department of Psychiatry and Psychotherapy, Ludwig-Maximilian University of Munich, Munich, Germany.
⁶ Department of Psychiatry and Psychotherapy, University Medical Center, Georg-August University Göttingen, Göttingen, Germany.
⁷ Institute of Human Genetics and Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
⁸ Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.
⁹ Hebrew SeniorLife Institute for Aging Research, Harvard Medical School, Boston, Massachusetts.
¹⁰ Program for Quantitative Genomics, Harvard School of Public Health, Boston, Massachusetts.
¹¹ Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
¹² Department of Psychiatry, University of California San Diego.
¹³ Department of Psychiatry and Psychotherapy, Charité-Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany.
¹⁴ Department of Biological Psychiatry and Neuroscience, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan.
¹⁵ Unit of Clinical Pharmacology, Hospital University Agency of Cagliari, Cagliari, Italy.
¹⁶ Unitat de Zoologia i Antropologia Biològica (Dpt Biologia Evolutiva, Ecologia i Ciències Ambientals), Facultat de Biologia and Institut de Biomedicina, University of Barcelona, Centro de Investigación Biomédica en Red de Salud Mental, Barcelona, Spain.
¹⁷ Department of Psychiatry, Mood Disorders Unit, Geneva University Hospitals, Geneva, Switzerland.
¹⁸ Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden, and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
¹⁹ 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.
²⁰ 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.
²¹ Department of Psychiatry and Psychotherapeutic Medicine, Research Unit for Bipolar Affective Disorder, Medical University of Graz, Graz, Austria.
²² Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.
²³ Department of Psychiatry and Psychology, Mayo Clinic, Rochester, Minnesota.
²⁴ The Neuromodulation Unit, McGill University Health Centre, Montreal, Canada.
²⁵ Department of Psychiatry and Center of Sleep Disorders, National Taiwan University Hospital, Taipei, Taiwan.
²⁶ Human Genomics Research Group, Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
²⁷ Douglas Mental Health University Institute, McGill University, Montreal, Canada.
²⁸ Psychiatric Genetic Unit, Poznan University of Medical Sciences, Poznan, Poland.
²⁹ Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
³⁰ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, Maryland.
³¹ Department of Psychiatry, University of Basel, Basel, Switzerland.
³² Neuroscience Research Australia, Sydney, New South Wales, Australia.
³³ School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia.
³⁴ Service de Psychiatrie, Hôpital Charles Perrens, Bordeaux, France.
³⁵ Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada.
³⁶ Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Bucharest, Romania.
³⁷ Mood Disorders Center of Ottawa, Ontario, Canada.
³⁸ Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Osaka, Japan.
³⁹ Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, Japan.
⁴⁰ Institut National de la Santé et de la Recherche Médicale Unité 955, Psychiatrie Translationnelle, Créteil, France.
⁴¹ Service de Psychiatrie et Psychologie Clinique, Centre Psychothérapique de Nancy, Université de Lorraine, Nancy, France.
⁴² Department of Public Health and Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
⁴³ Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Saitama, Japan.
⁴⁴ Department of Psychiatry, Psychosomatic Medicine, and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany.
⁴⁵ Department of Adult Psychiatry, Poznan University of Medical Sciences, Poznan, Poland.
⁴⁶ Department of Psychiatry and Psychotherapeutic Medicine, Landesklinikum Neunkirchen, Neunkirchen, Austria.
⁴⁷ Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
⁴⁸ Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the Gothenburg University, Gothenburg, Sweden.
⁴⁹ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁵⁰ Inserm U955, Translational Psychiatry Laboratory, Université Paris-Est-Créteil, Department of Psychiatry and Addictology of Mondor University Hospital, Assistance Publique-Hôpitaux de Paris, Hôpital Albert Chenevier-Henri Mondor, Pôle de Psychiatrie, Créteil, France.
⁵¹ Department of Pharmacy, Veterans Affairs San Diego Healthcare System, San Diego, California.
⁵² Department of Psychiatry, University of Perugia, Perugia, Italy.
⁵³ Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy.
⁵⁴ Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
⁵⁵ Department of Clinical Neurosciences, Karolinska Institutet, Stockholm, Sweden.
⁵⁶ Department of Psychiatry, Veterans Affairs San Diego Healthcare System, San Diego, California.
⁵⁷ Department of Psychiatry, Lindner Center of Hope and University of Cincinnati, Mason, Ohio.
⁵⁸ Mental Health Research Group, IMIM-Hospital del Mar, Barcelona, Catalonia, Spain.
⁵⁹ Centro de Investigación Biomédica en Red de Salud Mental, Instituto de Salud Carlos III, Madrid, Spain.
⁶⁰ Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
⁶¹ Neurosciences Section, Department of Medicine and Surgery, University of Salerno, Salerno, Italy.
⁶² Department of Psychiatry, Second University of Naples, Naples, Italy.
⁶³ National Institute of Mental Health, Klecany, Czech Republic.
⁶⁴ Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
⁶⁵ Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
⁶⁶ Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Medical Faculty, Technische Universität Dresden, Germany.
⁶⁷ Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada.
⁶⁸ Department of Psychiatry, Dokkyo University School of Medicine, Mibu, Tochigi, Japan.
⁶⁹ Bipolar Center Wiener Neustadt, Sigmund Freud University, Medical Faculty, Vienna, Austria.
⁷⁰ Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
⁷¹ School of Psychiatry, University of New South Wales, and Black Dog Institute, Sydney, New South Wales, Australia.
⁷² Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.

PMID: 29121268
PMCID: PMC5833535
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 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.

Trial registration: ClinicalTrials.gov NCT00001174.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: None reported.

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References

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1. Merikangas KR, Akiskal HS, Angst J, et al. . Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity Survey replication. Arch Gen Psychiatry. 2007;64(5):543-552. - PMC - PubMed
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[1] Merikangas KR, Jin R, He J-P, et al. . Prevalence and correlates of bipolar spectrum disorder in the World Mental Health Survey initiative. Arch Gen Psychiatry. 2011;68(3):241-251. - PMC - PubMed

[2] Merikangas KR, Jin R, He J-P, et al. . Prevalence and correlates of bipolar spectrum disorder in the World Mental Health Survey initiative. Arch Gen Psychiatry. 2011;68(3):241-251. - PMC - PubMed

[3] Merikangas KR, Akiskal HS, Angst J, et al. . Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity Survey replication. Arch Gen Psychiatry. 2007;64(5):543-552. - PMC - PubMed

[4] Merikangas KR, Akiskal HS, Angst J, et al. . Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity Survey replication. Arch Gen Psychiatry. 2007;64(5):543-552. - PMC - PubMed

[5] Ferrari AJ, Stockings E, Khoo JP, et al. . The prevalence and burden of bipolar disorder: findings from the Global Burden of Disease Study 2013. Bipolar Disord. 2016;18(5):440-450. - PubMed

[6] Ferrari AJ, Stockings E, Khoo JP, et al. . The prevalence and burden of bipolar disorder: findings from the Global Burden of Disease Study 2013. Bipolar Disord. 2016;18(5):440-450. - PubMed

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[8] Chesney E, Goodwin GM, Fazel S. Risks of all-cause and suicide mortality in mental disorders: a meta-review. World Psychiatry. 2014;13(2):153-160. - PMC - PubMed

[9] Grande I, Berk M, Birmaher B, Vieta E. Bipolar disorder. Lancet. 2016;387(10027):1561-1572. - PubMed

[10] Grande I, Berk M, Birmaher B, Vieta E. Bipolar disorder. Lancet. 2016;387(10027):1561-1572. - PubMed

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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

Affiliations

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

Authors

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Abstract

Conflict of interest statement

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