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

Hou, L. and Heilbronner, U. and Degenhardt, F. and Adli, M. and Akiyama, K. and Akula, N. and Ardau, R. and Arias, B. and Backlund, L. and Banzato, C. E. and Benabarre, A. and Bengesser, S. and Bhattacharjee, A. K. and Biernacka, J. M. and Birner, A. and Brichant-Petitjean, C. and Bui, E. T. and Cervantes, P. and Chen, G. B. and Chen, H. C. and Chillotti, C. and Cichon, S. and Clark, S. R. and Colom, F. and Cousins, D. A. and Cruceanu, C. and Czerski, P. M. and Dantas, C. R. and Dayer, A. and Etain, B. and Falkai, P. and Forstner, A. J. and Frisen, L. and Fullerton, J. M. and Gard, S. and Garnham, J. S. and Goes, F. S. and Grof, P. and Gruber, O. and Hashimoto, R. and Hauser, J. and Herms, S. and Hoffmann, P. and Hofmann, A. and Jamain, S. and Jimenez, E. and Kahn, J. P. and Kassem, L. and Kittel-Schneider, S. and Kliwicki, S. and Konig, B. and Kusumi, I. and Lackner, N. and Laje, G. and Landen, M. and Lavebratt, C. and Leboyer, M. and Leckband, S. G. and Jaramillo, C. A. and MacQueen, G. and Manchia, M. and Martinsson, L. and Mattheisen, M. and McCarthy, M. J. and McElroy, S. L. and Mitjans, M. and Mondimore, F. M. and Monteleone, P. and Nievergelt, C. M. and Nothen, M. M. and Osby, U. and Ozaki, N. and Perlis, R. H. and Pfennig, A. and Reich-Erkelenz, D. and Rouleau, G. A. and Schofield, P. R. and Schubert, K. O. and Schweizer, B. W. and Seemuller, F. and Severino, G. and Shekhtman, T. and Shilling, P. D. and Shimoda, K. and Simhandl, C. and Slaney, C. M. and Smoller, J. W. and Squassina, A. and Stamm, T. and Stopkova, P. and Tighe, S. K. and Tortorella, A. and Turecki, G. and Volkert, J. and Witt, S. and Wright, A. and Young, L. T. and Zandi, P. P. and Potash, J. B. and DePaulo, J. R. and Bauer, M. and Reininghaus, E. Z. and Novak, T. and Aubry, J. M. and Maj, M. and Baune, B. T. and Mitchell, P. B. and Vieta, E. and Frye, M. A. and Rybakowski, J. K. and Kuo, P. H. and Kato, T. and Grigoroiu-Serbanescu, M. and Reif, A. and Del Zompo, M. and Bellivier, F. and Schalling, M. and Wray, N. R. and Kelsoe, J. R. and Alda, M. and Rietschel, M. and McMahon, F. J. and Schulze, T. G.. (2016) Genetic variants associated with response to lithium treatment in bipolar disorder: a genome-wide association study. The Lancet, 387 (10023). pp. 1085-1093.

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Official URL: https://edoc.unibas.ch/61555/

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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 x 10(-8); rs78015114, p=1.31 x 10(-8); rs74795342, p=3.31 x 10(-9); and rs75222709, p=3.50 x 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.

Faculties and Departments:	03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Human Genetics (Cichon)
UniBasel Contributors:	Cichon, Sven
Item Type:	Article, refereed
Article Subtype:	Research Article
e-ISSN:	1474-547X
Note:	Publication type according to Uni Basel Research Database: Journal article
Related URLs:	Green Open Access
Identification Number:	doi: 10.1016/S0140-6736(16)00143-4 pmid: 26806518
Last Modified:	09 Apr 2019 16:27
Deposited On:	09 Apr 2019 16:27

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