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

Lookup NU author(s): Dr David Cousins

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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.


Publication metadata

Author(s): Hou LP, Heilbronner U, Degenhardt F, Adli M, Akiyama K, Akula N, Ardau R, Arias B, Backlund L, Banzato CEM, 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, Eacute;tain B, Falkai P, Forstner AJ, Frisen 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, Jimenez E, Kahn JP, Kassem L, Kittel-Schneider S, Kliwicki S, Konig B, Kusumi I, Lackner N, Laje G, Landen M, Lavebratt C, Leboyer M, Leckband SG, Jaramillo CAL, MacQueen G, Manchia M, Martinsson L, Mattheisen M, McCarthy MJ, McElroy SL, Mitjans M, Mondimore FM, Monteleone P, Nievergelt CM, Nothen MM, Ouml;sby U, Ozaki N, Perlis RH, Pfennig A, Reich-Erkelenz D, Rouleau GA, Schofield PR, Schubert KO, Schweizer BW, Seemuller 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, Novak 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

Publication type: Article

Publication status: Published

Journal: The Lancet

Year: 2016

Volume: 387

Issue: 10023

Pages: 1085-1093

Print publication date: 12/03/2016

Online publication date: 22/01/2016

Acceptance date: 01/01/1900

ISSN (print): 0140-6736

ISSN (electronic): 1474-547X

Publisher: Elsevier

URL: http://dx.doi.org/10.1016/S0140-6736(16)00143-4

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


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Funding

Funder referenceFunder name
BONFOR Programme of the University of Bonn, Germany
Dr-Lisa-Oehler-Foundation (Kassel, Germany)
German Federal Ministry of Education and Research (BMBF)
James Wah Fund
Land Steiermark
Project MATCH
Stanley Center for Psychiatric Research at the Broad Institute
Swedish Brain Foundation
Swedish Research Council
Alfried Krupp von Bohlen und Halbach-Stiftung
Deutsche Forschungsgemeinschaft
German Federal Ministry of Education and Research (BMBF) through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders) under e:Med Programme
Karolinska Institutet
Karolinska University Hospital
National Institute of Mental Health Intramural Research Program
Reuben Stoltzfus Bipolar Research Fund
Sardinia Regional Government POR Sardegna FSE Operational Program of the Autonomous Region of Sardinia, European Social Fund
Swiss National Science Foundation (NCCR Synapsy)
University of Antioquia
102-2314-B-002-117-MY3Taiwan Ministry of Science and Technology
2014SGR398Secretaria d'Universitats i Recerca del Departament d'Economia i Coneixement
1037196Australian NHMRC Program Grant
1078901Australian NHMRC Fellowships
32003B_125469Swiss National Science Foundation
5K02DA021237NIH from National Institute of Drug Abuse
2014SGR1636Secretaria d'Universitats i Recerca del Departament d'Economia i Coneixement
613602Australian NHMRC Fellowships
64410Canadian Institutes of Health Research
89/2012UEFISCDI, Romania
523-2011-3807Swedish Research Council
FOR2107Deutsche Forschungsgemeinschaft (DFG)
IGA NT13891Ministry of Health of the Czech Republic
MR/L006642/1Medical Research Council Clinician Scientist Fellowship Award
MST 99-2314-B-002-140-MY3Taiwan Ministry of Science and Technology
PI080247Centro de Investigacion en Red de Salud Mental (CIBERSAM) IDIBAPS
PI12/00018Centro de Investigacion en Red de Salud Mental (CIBERSAM) IDIBAPS
NCT00001174National Institute of Mental Health
NO 246/10-1Deutsche Forschungsgemeinschaft (DFG)
P50CA89392NIH from National Cancer Institute
RI 908/11-1Deutsche Forschungsgemeinschaft (DFG)
RI 908/7-1Deutsche Forschungsgemeinschaft (DFG)
PI1200906Centro de Investigacion en Red de Salud Mental (CIBERSAM) IDIBAPS
ZIA-MH00284311National Institute of Mental Health

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