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

Liping Hou; Urs Heilbronner; Franziska Degenhardt; Mazda Adli; Kazufumi Akiyama; Nirmala Akula; Raffaella Ardau; Bárbara Arias; Lena Backlund; Claudio E M Banzato; Antoni Benabarre; Susanne Bengesser; Abesh Kumar Bhattacharjee; Joanna M Biernacka; Armin Birner; Clara Brichant-Petitjean; Elise T Bui; Pablo Cervantes; Guo-Bo Chen; Hsi-Chung Chen; Caterina Chillotti; Sven Cichon; Scott R Clark; Francesc Colom; David A Cousins; Cristiana Cruceanu; Piotr M Czerski; Clarissa R Dantas; Alexandre Dayer; Bruno Étain; Peter Falkai; Andreas J Forstner; Louise Frisén; Janice M Fullerton; Sébastien Gard; Julie S Garnham; Fernando S Goes; Paul Grof; Oliver Gruber; Ryota Hashimoto; Joanna Hauser; Stefan Herms; Per Hoffmann; Andrea Hofmann; Stephane Jamain; Esther Jiménez; Jean-Pierre Kahn; Layla Kassem; Sarah Kittel-Schneider; Sebastian Kliwicki; Barbara König; Ichiro Kusumi; Nina Lackner; Gonzalo Laje; Mikael Landén; Catharina Lavebratt; Marion Leboyer; Susan G Leckband; Carlos A López Jaramillo; Glenda MacQueen; Mirko Manchia; Lina Martinsson; Manuel Mattheisen; Michael J McCarthy; Susan L McElroy; Marina Mitjans; Francis M Mondimore; Palmiero Monteleone; Caroline M Nievergelt; Markus M Nöthen; Urban Ösby; Norio Ozaki; Roy H Perlis; Andrea Pfennig; Daniela Reich-Erkelenz; Guy A Rouleau; Peter R Schofield; K Oliver Schubert; Barbara W Schweizer; Florian Seemüller; Giovanni Severino; Tatyana Shekhtman; Paul D Shilling; Kazutaka Shimoda; Christian Simhandl; Claire M Slaney; Jordan W Smoller; Alessio Squassina; Thomas Stamm; Pavla Stopkova; Sarah K Tighe; Alfonso Tortorella; Gustavo Turecki; Julia Volkert; Stephanie Witt; Adam Wright; L Trevor Young; Peter P Zandi; James B Potash; J Raymond DePaulo; Michael Bauer; Eva Z Reininghaus; Tomas Novák; Jean-Michel Aubry; Mario Maj; Bernhard T Baune; Philip B Mitchell; Eduard Vieta; Mark A Frye; Janusz K Rybakowski; Po-Hsiu Kuo; Tadafumi Kato; Maria Grigoroiu-Serbanescu; Andreas Reif; Maria Del Zompo; Frank Bellivier; Martin Schalling; Naomi R Wray; John R Kelsoe; Martin Alda; Marcella Rietschel; Francis J McMahon; Thomas G Schulze

doi:10.1016/S0140-6736(16)00143-4

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

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

Authors

Liping Hou¹, Urs Heilbronner², Franziska Degenhardt³, Mazda Adli⁴, Kazufumi Akiyama⁵, Nirmala Akula¹, Raffaella Ardau⁶, Bárbara Arias⁷, Lena Backlund⁸, Claudio E M Banzato⁹, Antoni Benabarre¹⁰, Susanne Bengesser¹¹, Abesh Kumar Bhattacharjee¹², Joanna M Biernacka¹³, Armin Birner¹¹, Clara Brichant-Petitjean¹⁴, Elise T Bui¹, Pablo Cervantes¹⁵, Guo-Bo Chen¹⁶, Hsi-Chung Chen¹⁷, Caterina Chillotti⁶, Sven Cichon¹⁸, Scott R Clark¹⁹, Francesc Colom¹⁰, David A Cousins²⁰, Cristiana Cruceanu²¹, Piotr M Czerski²², Clarissa R Dantas⁹, Alexandre Dayer²³, Bruno Étain²⁴, Peter Falkai²⁵, Andreas J Forstner³, Louise Frisén²⁶, Janice M Fullerton²⁷, Sébastien Gard²⁸, Julie S Garnham²⁹, Fernando S Goes³⁰, Paul Grof³¹, Oliver Gruber³², Ryota Hashimoto³³, Joanna Hauser²², Stefan Herms¹⁸, Per Hoffmann¹⁸, Andrea Hofmann³, Stephane Jamain²⁴, Esther Jiménez¹⁰, Jean-Pierre Kahn³⁴, Layla Kassem¹, Sarah Kittel-Schneider³⁵, Sebastian Kliwicki³⁶, Barbara König³⁷, Ichiro Kusumi³⁸, Nina Lackner¹¹, Gonzalo Laje¹, Mikael Landén³⁹, Catharina Lavebratt⁸, Marion Leboyer⁴⁰, Susan G Leckband⁴¹, Carlos A López Jaramillo⁴², Glenda MacQueen⁴³, Mirko Manchia⁴⁴, Lina Martinsson⁴⁵, Manuel Mattheisen⁴⁶, Michael J McCarthy⁴⁷, Susan L McElroy⁴⁸, Marina Mitjans⁷, Francis M Mondimore³⁰, Palmiero Monteleone⁴⁹, Caroline M Nievergelt¹², Markus M Nöthen³, Urban Ösby⁵⁰, Norio Ozaki⁵¹, Roy H Perlis⁵², Andrea Pfennig⁵³, Daniela Reich-Erkelenz⁵⁴, Guy A Rouleau⁵⁵, Peter R Schofield²⁷, K Oliver Schubert¹⁹, Barbara W Schweizer³⁰, Florian Seemüller²⁵, Giovanni Severino⁵⁶, Tatyana Shekhtman⁵⁷, Paul D Shilling¹², Kazutaka Shimoda⁵⁸, Christian Simhandl⁵⁹, Claire M Slaney²⁹, Jordan W Smoller⁵², Alessio Squassina⁵⁶, Thomas Stamm⁶⁰, Pavla Stopkova⁶¹, Sarah K Tighe⁶², Alfonso Tortorella⁶³, Gustavo Turecki²¹, Julia Volkert³⁵, Stephanie Witt⁶⁴, Adam Wright⁶⁵, L Trevor Young⁶⁶, Peter P Zandi⁶⁷, James B Potash⁶⁸, J Raymond DePaulo³⁰, Michael Bauer⁵³, Eva Z Reininghaus¹¹, Tomas Novák⁶¹, Jean-Michel Aubry²³, Mario Maj⁶³, Bernhard T Baune¹⁹, Philip B Mitchell⁶⁵, Eduard Vieta¹⁰, Mark A Frye⁶⁹, Janusz K Rybakowski³⁶, Po-Hsiu Kuo⁷⁰, Tadafumi Kato⁷¹, Maria Grigoroiu-Serbanescu⁷², Andreas Reif³⁵, Maria Del Zompo⁷³, Frank Bellivier¹⁴, Martin Schalling⁸, Naomi R Wray¹⁶, John R Kelsoe⁵⁷, Martin Alda⁷⁴, Marcella Rietschel⁶⁴, Francis J McMahon⁷⁵, Thomas G Schulze⁷⁶

Affiliations

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.

Publication types

Clinical Trial
Multicenter Study
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Bipolar Disorder / drug therapy
Bipolar Disorder / genetics*
Female
Genetic Variation
Genome-Wide Association Study
Genotype
Glial Cell Line-Derived Neurotrophic Factor Receptors / genetics
Humans
Lithium Compounds / therapeutic use*
Male
Middle Aged
Phenotype
Polymorphism, Single Nucleotide / genetics*
Prospective Studies
Treatment Outcome

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

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