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JAMA Psychiatry. 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), Amare AT1, Schubert KO1,2, Hou L3, Clark SR1, Papiol S4,5, Heilbronner U4,6, Degenhardt F7, Tekola-Ayele F8, Hsu YH9,10,11, Shekhtman T12, Adli M13, Akula N3, Akiyama K14, Ardau R15, Arias B16, Aubry JM17, Backlund L18, Bhattacharjee AK12, Bellivier F19, Benabarre A20, Bengesser S21, Biernacka JM22,23, Birner A21, Brichant-Petitjean C19, Cervantes P24, Chen HC25, Chillotti C15, Cichon S7,26, Cruceanu C27, Czerski PM28, Dalkner N21, Dayer A17, Del Zompo M29, DePaulo JR30, Étain B19, Falkai P5, Forstner AJ7,26,31, Frisen L18, Frye MA23, Fullerton JM32,33, Gard S34, Garnham JS35, Goes FS30, Grigoroiu-Serbanescu M36, Grof P37, Hashimoto R38,39, Hauser J28, Herms S7,26, Hoffmann P7,26, Hofmann A7, Jamain S40, Jiménez E20, Kahn JP41, Kassem L3, Kuo PH42, Kato T43, Kelsoe J12, Kittel-Schneider S44, Kliwicki S45, König B46, Kusumi I47, Laje G3, Landén M48,49, Lavebratt C18, Leboyer M50, Leckband SG51, Tortorella A52, Manchia M53,54, Martinsson L55, McCarthy MJ12,56, McElroy S57, Colom F20,58, Mitjans M59,60, Mondimore FM30, Monteleone P61,62, Nievergelt CM12, Nöthen MM7, Novák T63, O'Donovan C35, Ozaki N64, Ösby U65, Pfennig A66, Potash JB30, Reif A43, Reininghaus E21, Rouleau GA67, Rybakowski JK44, Schalling M18, Schofield PR32,33, Schweizer BW30, Severino G29, Shilling PD18, Shimoda K68, Simhandl C69, Slaney CM35, Squassina A29, Stamm T13, Stopkova P63, Maj M62, Turecki G27, Vieta E20, Volkert J44, Witt S70, Wright A71, Zandi PP72, Mitchell PB71, Bauer M66, Alda M35, Rietschel M70, McMahon FJ3, Schulze TG3,4,6,30,70, Baune BT1.

Author information

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.

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.

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