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

Hou, Liping, Heilbronner, Urs, Degenhardt, Franziska, Adli, Mazda, Akiyama, Kazufumi, Akula, Nirmala, Ardau, Raffaella, Arias, Bárbara, Backlund, Lena, Banzato, Claudio E. M., Benabarre, Antoni, Bengesser, Susanne, Bhattacharjee, Abesh Kumar, Biernacka, Joanna M., Birner, Armin, Brichant-Petitjean, Clara, Bui, Elise T., Cervantes, Pablo, Chen, Guo-Bo, Chen, Hsi-Chung, Chillotti, Caterina, Cichon, Sven, Clark, Scott R., Colom, Francesc, Cousins, David A., Cruceanu, Cristiana, Czerski, Piotr M., Dantas, Clarissa R., Dayer, Alexandre, Etain, Bruno, Falkai, Peter, Forstner, Andreas J., Frisen, Louise, Fullerton, Janice M., Gard, Sébastien, Garnham, Julie S., Goes, Fernando S., Grof, Paul, Gruber, Oliver, Hashimoto, Ryota, Hauser, Joanna, Herms, Stefan, Hoffmann, Per, Hofmann, Andrea, Jamain, Stephane, Jimenez, Esther, Kahn, Jean-Pierre, Kassem, Layla, Kittel-Schneider, Sarah, Kliwicki, Sebastian, Konig, Barbara, Kusumi, Ichiro, Lackner, Nina, Laje, Gonzalo, Landen, Mikael, Lavebratt, Catharina, Leboyer, Marion, Leckband, Susan G., Jaramillo, Carlos A López, MacQueen, Glenda, Manchia, Mirko, Martinsson, Lina, Mattheisen, Manuel, McCarthy, Michael J., McElroy, Susan L., Mitjans, Marina, Mondimore, Francis M., Monteleone, Palmiero, Nievergelt, Caroline M., Nothen, Markus M., Osby, Urban, Ozaki, Norio, Perlis, Roy H., Pfennig, Andrea, Reich-Erkelenz, Daniela, Rouleau, Guy A., Schofield, Peter R., Schubert, K. Oliver, Schweizer, Barbara W., Seemuller, Florian, Severino, Giovanni, Shekhtman, Tatyana, Shilling, Paul D., Shimoda, Kazutaka, Simhandl, Christian, Slaney, Claire M., Smoller, Jordan W., Squassina, Alessio, Stamm, Thomas, Stopkova, Pavla, Tighe, Sarah K., Tortorella, Alfonso, Turecki, Gustavo, Volkert, Julia, Witt, Stephanie, Wright, Adam, Young, L. Trevor, Zandi, Peter P., Potash, James B., DePaulo, J. Raymond, Bauer, Michael, Reininghaus, Eva Z., Novak, Tomas, Aubry, Jean-Michel, Maj, Mario, Baune, Bernhard T., Mitchell, Philip B., Vieta, Eduard, Frye, Mark A., Rybakowski, Janusz K., Kuo, Po-Hsiu, Kato, Tadafumi, Grigoroiu-Serbanescu, Maria, Reif, Andreas, Del Zompo, Maria, Bellivier, Frank, Schalling, Martin, Wray, Naomi R., Kelsoe, John R., Alda, Martin, Rietschel, Marcella, McMahon, Francis J. and Schulze, Thomas G. (2016) Genetic variants associated with response to lithium treatment in bipolar disorder: a genome-wide association study. The Lancet, 387 10023: 1085-1093. doi:10.1016/S0140-6736(16)00143-4


Author Hou, Liping
Heilbronner, Urs
Degenhardt, Franziska
Adli, Mazda
Akiyama, Kazufumi
Akula, Nirmala
Ardau, Raffaella
Arias, Bárbara
Backlund, Lena
Banzato, Claudio E. M.
Benabarre, Antoni
Bengesser, Susanne
Bhattacharjee, Abesh Kumar
Biernacka, Joanna M.
Birner, Armin
Brichant-Petitjean, Clara
Bui, Elise T.
Cervantes, Pablo
Chen, Guo-Bo
Chen, Hsi-Chung
Chillotti, Caterina
Cichon, Sven
Clark, Scott R.
Colom, Francesc
Cousins, David A.
Cruceanu, Cristiana
Czerski, Piotr M.
Dantas, Clarissa R.
Dayer, Alexandre
Etain, Bruno
Falkai, Peter
Forstner, Andreas J.
Frisen, Louise
Fullerton, Janice M.
Gard, Sébastien
Garnham, Julie S.
Goes, Fernando S.
Grof, Paul
Gruber, Oliver
Hashimoto, Ryota
Hauser, Joanna
Herms, Stefan
Hoffmann, Per
Hofmann, Andrea
Jamain, Stephane
Jimenez, Esther
Kahn, Jean-Pierre
Kassem, Layla
Kittel-Schneider, Sarah
Kliwicki, Sebastian
Konig, Barbara
Kusumi, Ichiro
Lackner, Nina
Laje, Gonzalo
Landen, Mikael
Lavebratt, Catharina
Leboyer, Marion
Leckband, Susan G.
Jaramillo, Carlos A López
MacQueen, Glenda
Manchia, Mirko
Martinsson, Lina
Mattheisen, Manuel
McCarthy, Michael J.
McElroy, Susan L.
Mitjans, Marina
Mondimore, Francis M.
Monteleone, Palmiero
Nievergelt, Caroline M.
Nothen, Markus M.
Osby, Urban
Ozaki, Norio
Perlis, Roy H.
Pfennig, Andrea
Reich-Erkelenz, Daniela
Rouleau, Guy A.
Schofield, Peter R.
Schubert, K. Oliver
Schweizer, Barbara W.
Seemuller, Florian
Severino, Giovanni
Shekhtman, Tatyana
Shilling, Paul D.
Shimoda, Kazutaka
Simhandl, Christian
Slaney, Claire M.
Smoller, Jordan W.
Squassina, Alessio
Stamm, Thomas
Stopkova, Pavla
Tighe, Sarah K.
Tortorella, Alfonso
Turecki, Gustavo
Volkert, Julia
Witt, Stephanie
Wright, Adam
Young, L. Trevor
Zandi, Peter P.
Potash, James B.
DePaulo, J. Raymond
Bauer, Michael
Reininghaus, Eva Z.
Novak, Tomas
Aubry, Jean-Michel
Maj, Mario
Baune, Bernhard T.
Mitchell, Philip B.
Vieta, Eduard
Frye, Mark A.
Rybakowski, Janusz K.
Kuo, Po-Hsiu
Kato, Tadafumi
Grigoroiu-Serbanescu, Maria
Reif, Andreas
Del Zompo, Maria
Bellivier, Frank
Schalling, Martin
Wray, Naomi R.
Kelsoe, John R.
Alda, Martin
Rietschel, Marcella
McMahon, Francis J.
Schulze, Thomas G.
Title Genetic variants associated with response to lithium treatment in bipolar disorder: a genome-wide association study
Journal name The Lancet   Check publisher's open access policy
ISSN 1474-547X
0140-6736
Publication date 2016-03
Year available 2016
Sub-type Article (original research)
DOI 10.1016/S0140-6736(16)00143-4
Open Access Status Not yet assessed
Volume 387
Issue 10023
Start page 1085
End page 1093
Total pages 9
Place of publication London, United Kingdom
Publisher Lancet Publishing Group
Collection year 2017
Language eng
Formatted 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.
Keyword Lithium
Bipolar disorder
Psychiatric illness
Bipolar disorder types I and II
Mental health
Mood stabilisers
Genetic variants
Lithium response
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Queensland Brain Institute Publications
 
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