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

Hou L, Heilbronner U, Degenhardt F, Adli M, Akiyama K, Akula N, Ardau R, Arias B, Backlund L, Banzato CE, Benabarre A, Bengesser S, Bhattacharjee AK, Biernacka JM, Birner A, Brichant-Petitjean C, Bui ET, Cervantes P, Chen GB, Chen HC, Chillotti C, Cichon S, Clark SR, Colom F, Cousins DA, Cruceanu C, Czerski PM, Dantas CR, Dayer A, Étain B, Falkai P, Forstner AJ, Frisén L, Fullerton JM, Gard S, Garnham JS, Goes FS, Grof P, Gruber O, Hashimoto R, Hauser J, Herms S, Hoffmann P, Hofmann A, Jamain S, Jiménez E, Kahn JP, Kassem L, Kittel-Schneider S, Kliwicki S, König B, Kusumi I, Lackner N, Laje G, Landén M, Lavebratt C, Leboyer M, Leckband SG, Jaramillo CA, Macqueen G, Manchia M, Martinsson L, Mattheisen M, McCarthy MJ, McElroy SL, Mitjans M, Mondimore FM, Monteleone P, Nievergelt CM, Nöthen MM, Ösby U, Ozaki N, Perlis RH, Pfennig A, Reich-Erkelenz D, Rouleau GA, Schofield PR, Schubert KO, Schweizer BW, Seemüller F, Severino G, Shekhtman T, Shilling PD, Shimoda K, Simhandl C, Slaney CM, Smoller JW, Squassina A, Stamm T, Stopkova P, Tighe SK, Tortorella A, Turecki G, Volkert J, Witt S, Wright A, Young LT, Zandi PP, Potash JB, Depaulo JR, Bauer M, Reininghaus EZ, Novák T, Aubry JM, Maj M, Baune BT, Mitchell PB, Vieta E, Frye MA, Rybakowski JK, Kuo PH, Kato T, Grigoroiu-Serbanescu M, Reif A, Del Zompo M, Bellivier F, Schalling M, Wray NR, Kelsoe JR, Alda M, Rietschel M, McMahon FJ, Schulze TG (2016)

Publication Type: Journal article

Publication year: 2016

Journal

Book Volume: 387

Pages Range: 1085-1093

Journal Issue: 10023

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

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.

Involved external institutions

Universitätsklinikum Frankfurt am Main (KGU) Germany (DE) Poznan University of Medical Sciences / Uniwersytet Medyczny im. Karola Marcinkowskiego w Poznaniu Poland (PL) Università degli Studi di Cagliari Italy (IT) Charité - Universitätsmedizin Berlin Germany (DE) National Institute of Mental Health (NIMH) / Národní ústav duševního zdraví (NUDZ) Czech Republic (CZ) University of Iowa United States (USA) (US) Università degli studi della Campania Luigi Vanvitelli Italy (IT) Douglas Mental Health University Institute Canada (CA) Ruprecht-Karls-Universität Heidelberg Germany (DE) University of New South Wales (UNSW) Australia (AU) University of Toronto Canada (CA) Johns Hopkins University (JHU) United States (USA) (US) Rheinische Friedrich-Wilhelms-Universität Bonn Germany (DE) Institut Mondor de Recherche Biomédicale France (FR) Universitat de Barcelona (UB) / University of Barcelona Spain (ES) Université de Lorraine France (FR) National Institute of Mental Health Information Resource Center United States (USA) (US) Medizinische Universität Graz Austria (AT) Massachusetts General Hospital United States (USA) (US) Karolinska University Hospital / Karolinska Universitetssjukhuset Sweden (SE) Universidade Estadual de Campinas (UNICAMP) / University of Campinas Brazil (BR) Mayo Clinic United States (USA) (US) Université Paris Cité France (FR) McGill University Health Centre (MUHC) / Centre universitaire de santé McGill Canada (CA) University of Queensland Australia (AU) National Taiwan University Hospital (NTUH) / 國立台灣大學醫學院附設醫院 Taiwan (TW) University of Adelaide Australia (AU) Newcastle University United Kingdom (GB) Klinikum der Universität München (LMU Klinikum) Germany (DE) Dokkyo Medical University Japan (JP) Sahlgrenska University Hospital / Sahlgrenska Universitetssjukhuset Sweden (SE) Università degli Studi di Salerno Italy (IT) Nagoya University / 名古屋大学 Japan (JP) Hospital Albert Chenevier Ap-Hp / Hôpital Albert Chenevier AP-HP Paris France (FR) Universidad de Antioquía (UDEA) Colombia (CO) University of Calgary Canada (CA) Karolinska Institute Sweden (SE) Universitätsklinikum Carl Gustav Carus Dresden Germany (DE) Aarhus University Denmark (DK) VA San Diego Healthcare System United States (USA) (US) University of Cincinnati United States (USA) (US) Geneva University Hospitals / Hôpitaux universitaires de Genève (HUG) Switzerland (CH) National Taiwan University (NTU) Taiwan (TW) RIKEN Center for Brain Science (CBS) Japan (JP) "Prof. Dr. Alexandru Obregia" Clinical Hospital of Psychiatry / Spitalul Clinic de Psihiatrie Prof. Dr. Alexandru Obregia Romania (RO) Veterans Health Administration (VHA) United States (USA) (US) Dalhousie University Canada (CA) Neuroscience Research Australia NeuRA Australia (AU) Centre Hospitalier Charles Perrens (CHCP) France (FR) Mood Disorders Ottawa Canada (CA) Universitätsklinikum Göttingen Germany (DE) Osaka University / 大阪大学 Japan (JP) Montreal Neurological Institute and Hospital (MNI, The Neuro) Canada (CA) BIPOLAR Zentrum Wiener Neustadt Austria (AT)

How to cite

APA:

Hou, L., Heilbronner, U., Degenhardt, F., Adli, M., Akiyama, K., Akula, N.,... Schulze, T.G. (2016). Genetic variants associated with response to lithium treatment in bipolar disorder: A genome-wide association study. The Lancet, 387(10023), 1085-1093. https://doi.org/10.1016/S0140-6736(16)00143-4

MLA:

Hou, Liping, et al. "Genetic variants associated with response to lithium treatment in bipolar disorder: A genome-wide association study." The Lancet 387.10023 (2016): 1085-1093.

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