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Lancet. 2016 Mar 12;387(10023):1085-1093. doi: 10.1016/S0140-6736(16)00143-4. Epub 2016 Jan 22.

Genetic variants associated with response to lithium treatment in bipolar disorder: a genome-wide association study.

Hou L1, Heilbronner U2, Degenhardt F3, Adli M4, Akiyama K5, Akula N1, Ardau R6, Arias B7, Backlund L8, Banzato CEM9, Benabarre A10, Bengesser S11, Bhattacharjee AK12, Biernacka JM13, Birner A11, Brichant-Petitjean C14, Bui ET1, Cervantes P15, Chen GB16, Chen HC17, Chillotti C6, Cichon S18, Clark SR19, Colom F10, Cousins DA20, Cruceanu C21, Czerski PM22, Dantas CR9, Dayer A23, Étain B24, Falkai P25, Forstner AJ3, Frisén L26, Fullerton JM27, Gard S28, Garnham JS29, Goes FS30, Grof P31, Gruber O32, Hashimoto R33, Hauser J22, Herms S18, Hoffmann P18, Hofmann A3, Jamain S24, Jiménez E10, Kahn JP34, Kassem L1, Kittel-Schneider S35, Kliwicki S36, König B37, Kusumi I38, Lackner N11, Laje G1, Landén M39, Lavebratt C8, Leboyer M40, Leckband SG41, Jaramillo CAL42, MacQueen G43, Manchia M44, Martinsson L45, Mattheisen M46, McCarthy MJ47, McElroy SL48, Mitjans M7, Mondimore FM30, Monteleone P49, Nievergelt CM12, Nöthen MM3, Ösby U50, Ozaki N51, Perlis RH52, Pfennig A53, Reich-Erkelenz D54, Rouleau GA55, Schofield PR27, Schubert KO19, Schweizer BW30, Seemüller F25, Severino G56, Shekhtman T57, Shilling PD12, Shimoda K58, Simhandl C59, Slaney CM29, Smoller JW52, Squassina A56, Stamm T60, Stopkova P61, Tighe SK62, Tortorella A63, Turecki G21, Volkert J35, Witt S64, Wright A65, Young LT66, Zandi PP67, Potash JB68, DePaulo JR30, Bauer M53, Reininghaus EZ11, Novák T61, Aubry JM23, Maj M63, Baune BT19, Mitchell PB65, Vieta E10, Frye MA69, Rybakowski JK36, Kuo PH70, Kato T71, Grigoroiu-Serbanescu M72, Reif A35, Del Zompo M73, Bellivier F14, Schalling M8, Wray NR16, Kelsoe JR57, Alda M74, Rietschel M64, McMahon FJ75, Schulze TG76.

Author information

1
Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health & Human Services, Bethesda, MD, USA.
2
Institute of Psychiatric Phenomics and Genomics, Ludwig-Maximilians-University Munich, Munich, Germany; Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August University Göttingen, Göttingen, Germany.
3
Institute of Human Genetics, University of Bonn and Department of Genomics, Life & Brain Center, Bonn, Germany.
4
Department of Psychiatry and Psychotherapy, Charité-Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany; Fliedner Klinik Berlin, Center for Psychiatry, Psychotherapy and Psychosomatic Medicine, Berlin, Germany.
5
Department of Biological Psychiatry and Neuroscience, Dokkyo Medical University School of Medicine, Mibu, Japan.
6
Unit of Clinical Pharmacology, Hospital University Agency of Cagliari, Cagliari, Italy.
7
Department of Biologia Animal, Unitat d'Antropologia (Dp Biología Animal), Facultat de Biologia and Institut de Biomedicina (IBUB), Universitat de Barcelona, CIBERSAM, Barcelona, Catalonia, Spain.
8
Department of Molecular Medicine and Surgery, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
9
Department of Psychiatry, University of Campinas (Unicamp), Campinas, Brazil.
10
Bipolar Disorder Program, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain.
11
Neurobiological Background and Anthropometrics in Bipolar Affective Disorder, Department of Psychiatry, Medical University of Graz, Graz, Austria.
12
Department of Psychiatry, University of California San Diego, San Diego, CA, USA.
13
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA; Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
14
INSERM UMR-S 1144-Université Paris Diderot Pôle de Psychiatrie, AP-HP, Groupe Hospitalier Lariboisière-F Widal, Paris, France.
15
The Neuromodulation Unit, McGill University Health Centre, Montreal, QC, Canada.
16
The University of Queensland, Queensland Brain Institute, Brisbane, Queensland, QLD, Australia.
17
Department of Psychiatry & Center of Sleep Disorders, National Taiwan University Hospital, Taipei, Taiwan.
18
Institute of Human Genetics, University of Bonn and Department of Genomics, Life & Brain Center, Bonn, Germany; Human Genomics Research Group, Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
19
Discipline of Psychiatry, University of Adelaide, Adelaide, SA, Australia.
20
Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, UK.
21
Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada.
22
Psychiatric Genetic Unit, Poznan University of Medical Sciences, Poznan, Poland.
23
Department of Mental Health and Psychiatry, Mood Disorders Unit-Geneva University Hospitals, Geneva, Switzerland.
24
Inserm U955, Psychiatrie Translationnelle, Créteil, France.
25
Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, Munich, Germany.
26
Department of Molecular Medicine and Surgery, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden; Department of Clinical Neuroscience, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden; Child and Adolescent Psychiatry Research Center, Stockholm, Sweden.
27
Mental Illness Research Theme, Neuroscience Research Australia, Sydney, NSW, Australia; School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
28
Pôle de Psychiatrie Générale Universitaire, Centre Hospitalier Charles Perrens, Bordeaux, France.
29
Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, NS, Canada.
30
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, USA.
31
Mood Disorders Center of Ottawa, Ottawa, ON, Canada.
32
Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August University Göttingen, Göttingen, Germany.
33
Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Osaka, Japan.
34
Service de Psychiatrie et Psychologie Clinique, Centre Psychothérapique de Nancy-Laxou-Université de Lorraine, Nancy, France.
35
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany.
36
Department of Adult Psychiatry, Poznan University of Medical Sciences, Poznan, Poland.
37
Department of Psychiatry and Psychotherapeutic Medicine, Landesklinikum Neunkirchen, Neunkirchen, Austria.
38
Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
39
Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the Gothenburg University, Gothenburg, Sweden; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
40
Assistance Publique-Hôpitaux de Paris, Hôpital Albert Chenevier-Henri Mondor, Pôle de Psychiatrie, Créteil, France.
41
Department of Molecular Medicine and Surgery, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden; Department of Pharmacy, VA San Diego Healthcare System, San Diego, CA, USA.
42
Department of Psychiatry, University of Antioquia, Medellín, Medellín, Colombia.
43
Department of Psychiatry, University of Calgary, Calgary, AB, Canada.
44
Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy; Department of Pharmacology, Dalhousie University, Halifax, NS, Canada.
45
Department of Clinical Neurosciences, Karolinska Institutet, Stockholm, Sweden.
46
Department of Biomedicine, Aarhus University, Aarhus, Denmark.
47
Department of Psychiatry, VA San Diego Healthcare System, San Diego, CA, USA.
48
Department of Psychiatry, Lindner Center of Hope, University of Cincinnati, Mason, OH, USA.
49
Neurosciences Section, Department of Medicine and Surgery, University of Salerno, Salerno, Italy; Department of Psychiatry, University of Naples SUN, Naples, Italy.
50
Department of Neurobiology, Care sciences, and Society, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
51
Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
52
Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
53
Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Medical Faculty, Technische Universität Dresden, Dresden, Germany.
54
Institute of Psychiatric Phenomics and Genomics, Ludwig-Maximilians-University Munich, Munich, Germany.
55
Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada.
56
Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
57
Veterans Administration, San Diego Healthcare System, San Diego, CA, USA; Department of Psychiatry, University of California San Diego, San Diego, CA, USA.
58
Department of Psychiatry, Dokkyo Medical University School of Medicine, Mibu, Japan.
59
Bipolar Center Wiener Neustadt, Wiener Neustadt, Austria.
60
Department of Psychiatry and Psychotherapy, Charité-Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany.
61
National Institute of Mental Health, Klecany, Czech Republic.
62
Department of Psychiatry, University of Iowa, Iowa City, IA, USA; University of Iowa Carver College of Medicine and University of Iowa College of Public Health, VA Quality Scholars Program, Iowa City VA Hospital, Iowa City, IA, USA.
63
Department of Psychiatry, University of Naples SUN, Naples, Italy.
64
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
65
School of Psychiatry, University of New South Wales, and Black Dog Institute, Sydney, NSW, Australia.
66
Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
67
Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
68
Department of Psychiatry, University of Iowa, Iowa City, IA, USA.
69
Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
70
Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taipei, Taiwan.
71
Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Saitama, Japan.
72
Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Psychiatric Hospital, Bucharest, Romania.
73
Unit of Clinical Pharmacology, Hospital University Agency of Cagliari, Cagliari, Italy; Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
74
Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, NS, Canada; National Institute of Mental Health, Klecany, Czech Republic.
75
Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health & Human Services, Bethesda, MD, USA. Electronic address: mcmahonf@mail.nih.gov.
76
Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health & Human Services, Bethesda, MD, USA; Institute of Psychiatric Phenomics and Genomics, Ludwig-Maximilians-University Munich, Munich, Germany; Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August University Göttingen, Göttingen, Germany; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, USA; Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany. Electronic address: thomas.schulze@med.uni-muenchen.de.

Abstract

BACKGROUND:

Lithium is a first-line treatment in bipolar disorder, but individual response is variable. Previous studies have suggested that lithium response is a heritable trait. However, no genetic markers of treatment response have been reproducibly identified.

METHODS:

Here, we report the results of a genome-wide association study of lithium response in 2563 patients collected by 22 participating sites from the International Consortium on Lithium Genetics (ConLiGen). Data from common single nucleotide polymorphisms (SNPs) were tested for association with categorical and continuous ratings of lithium response. Lithium response was measured using a well established scale (Alda scale). Genotyped SNPs were used to generate data at more than 6 million sites, using standard genomic imputation methods. Traits were regressed against genotype dosage. Results were combined across two batches by meta-analysis.

FINDINGS:

A single locus of four linked SNPs on chromosome 21 met genome-wide significance criteria for association with lithium response (rs79663003, p=1·37 × 10(-8); rs78015114, p=1·31 × 10(-8); rs74795342, p=3·31 × 10(-9); and rs75222709, p=3·50 × 10(-9)). In an independent, prospective study of 73 patients treated with lithium monotherapy for a period of up to 2 years, carriers of the response-associated alleles had a significantly lower rate of relapse than carriers of the alternate alleles (p=0·03268, hazard ratio 3·8, 95% CI 1·1-13·0).

INTERPRETATION:

The response-associated region contains two genes for long, non-coding RNAs (lncRNAs), AL157359.3 and AL157359.4. LncRNAs are increasingly appreciated as important regulators of gene expression, particularly in the CNS. Confirmed biomarkers of lithium response would constitute an important step forward in the clinical management of bipolar disorder. Further studies are needed to establish the biological context and potential clinical utility of these findings.

FUNDING:

Deutsche Forschungsgemeinschaft, National Institute of Mental Health Intramural Research Program.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT00001174.

PMID:
26806518
PMCID:
PMC4814312
DOI:
10.1016/S0140-6736(16)00143-4
[Indexed for MEDLINE]
Free PMC Article

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