• Liping Hou, Urs Heilbronner, Franziska Degenhardt, Mazda Adli, Kazufumi Akiyama, Nirmala Akula, Raffaella Ardau, Bárbara Arias, Lena Backlund, BanzatoClaudio E MCEMDepartment of Psychiatry, University of Campinas (Unicamp), Campinas, Brazil., 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, JaramilloCarlos A LópezCALDepartment of Psychiatry, University of Antioquia, Medellín, Medellín, Colombia., 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, and Thomas G Schulze.
• Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health & Human Services, Bethesda, MD, USA.
• Lancet. 2016 Mar 12; 387 (10023): 1085-1093.

BackgroundLithium 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.MethodsHere, 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.FindingsA 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).InterpretationThe 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.FundingDeutsche Forschungsgemeinschaft, National Institute of Mental Health Intramural Research Program.Copyright © 2016 Elsevier Ltd. All rights reserved.

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