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 ChenCaterina 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

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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.

Original languageEnglish (US)
Pages (from-to)1085-1093
Number of pages9
JournalThe Lancet
Volume387
Issue number10023
DOIs
StatePublished - Mar 12 2016

ASJC Scopus subject areas

  • Medicine(all)

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    Hou, L., Heilbronner, U., Degenhardt, F., Adli, M., Akiyama, K., Akula, N., Ardau, R., Arias, B., Backlund, L., Banzato, C. E. M., Benabarre, A., Bengesser, S., Bhattacharjee, A. K., Biernacka, J. M., Birner, A., Brichant-Petitjean, C., Bui, E. T., Cervantes, P., Chen, G. B., ... 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