Influence of genetic variants on the response to lithium treatment in bipolar disorder

   Bipolar disorder (BPD) is a major psychiatric illness with a chronic recurrent course, ranked among the leading disabling diseases worldwide. Lithium medication remains a first-line treatment option among BPD patients despite varying outcomes in treatment response. About two-thirds of BPD patients do not achieve full remission with lithium treatment. Significant genetic contributions have been suggested to account for part of the inter-individual differences in treatment response. The identification of such differences might allow for a better selection of treatments for BPD patients and facilitate the development of novel treatments for BPD in the future.

   The assessment of the response to lithium maintenance treatment in BPD is complicated by variable lengths of treatment, an unpredictable clinical course, and often inconsistent compliance. A rating scale (called the Alda scale) was previously developed to reliably and accurately assess lithium treatment response. Given the particular difficulties in obtaining long-term data of sufficient quality to adequately define treatment response, there is a strong need for groups to work together to jointly assemble and analyze cohorts to obtain replicable findings for follow-up studies. The Alda scale has been validated in an international collaboration network, the Consortium on Lithium Genetics (ConLiGen), for which we contribute as one of the member sites.

   A positive lithium response has previously been reported to be associated with several genetic variants, including variations in chromosome 4q32, core clock genes, GRIA2, and GADL1. However, none of these findings have been replicated in other studies. With the joint efforts of 22 international sites with samples from 2563 BPD patients and the use of a standard assessment scale for treatment response in the ConLiGen, we adopted a genome-wide association study design and performed whole-genome
pharmacogenetic analyses. We found that a single locus of four linked markers on chromosome 21 met genome-wide significance criteria for association with lithium response (the smallest p-value=3.31 × 10-9, Figure 1). This gene has not been previously associated with any treatment response-related traits and is located in a gene transcribing a long non-coding RNA (lncRNA), namely, AL157359.3, in this predominantly European sample. In an independent prospective study of 73 patients treated with lithium monotherapy for a period of up to 2 years, we replicated this finding, showing that carriers of the response-associated alleles had a significantly lower rate of relapse than non-carriers.

This is by far the largest genome-wide association study of lithium response in BPD published to date with significant results, and the main finding is an association with a non-protein coding gene. This finding provides some clues for lithium’s mechanism of action in BPD, although replication in large independent samples is preferable. There has been an increasing appreciation of the role of lncRNAs in gene regulation, especially in the central nervous system. Nevertheless, the exact function of the identified loci is unknown. Thus, the clinical importance of these findings might still be limited by insufficient knowledge of the function of this gene and its impact on pharmacokinetics and drug mechanisms. Notably, the identified locus showed no prominent effect on lithium response in samples of Asian ancestry in the ConLiGen (i.e., Japanese and Taiwanese samples). Within the Asian cohort, a different marker in the GFRA2 gene that codes for a glial cell line-derived neurotrophic factor receptor showed a suggestive association (p-value=2.1×10-7). This marker did not pass quality control in the European samples, indicating the relevance of searching for ethnic group-specific genetic variants. Furthermore, the necessary next step to uncover the underlying mechanisms of lithium treatment will be to test the functions of identified variants in cellular and animal models, eventually leading to better treatment options that benefit clinical patients.

Figure 1. Regional association plot of the region on chromosome 21 in which the genome-wide significant SNPs are located. Association p values are plotted as points; colors indicate degree of linkage disequilibrium with index SNP (violet). Local recombination rate is shown as a solid blue line. Genes are indicated as straight blue lines labelled with gene names. Mb=megabase. cM=centimorgan. SNP=single nucleotide polymorphism.

1. Mirko Manchia, Mazda Adli, Nirmala Akula, Raffaella Ardau, Jean-Michel Aubry, Lena Backlund, Claudio Em. Banzato, Bernhard T. Baune, Frank Bellivier, Susanne Bengesser, Joanna M. Biernacka, Clara Brichant-Petitjean, Elise Bui, Cynthia V. Calkin, Andrew Tai Ann Cheng, Caterina Chillotti, Sven Cichon, Scott Clark, Piotr M. Czerski, Clarissa Dantas, Maria Del Zompo, J. Raymond Depaulo, Sevilla D. Detera-Wadleigh, Bruno Etain, Peter Falkai, Louise Frisén, Mark A. Frye, Jan Fullerton, Sébastien Gard, Julie Garnham, Fernando S. Goes, Paul Grof, Oliver Gruber, Ryota Hashimoto, Joanna Hauser, Urs Heilbronner, Rebecca Hoban, Liping Hou, Stéphane Jamain, Jean-Pierre Kahn, Layla Kassem, Tadafumi Kato, John R. Kelsoe, Sarah Kittel-Schneider, Sebastian Kliwicki, Po-Hsiu Kuo, Ichiro Kusumi, Gonzalo Laje, Catharina Lavebratt, Marion Leboyer, Susan G. Leckband, Carlos A. López Jaramillo, Mario Maj, Alain Malafosse, Lina Martinsson, Takuya Masui, Philip B. Mitchell, Frank Mondimore, Palmiero Monteleone, Audrey Nallet, Maria Neuner, Tomás Novák, Claire O’Donovan, Urban Ösby, Norio Ozaki, Roy H. Perlis, Andrea Pfennig, James B. Potash, Daniela Reich-Erkelenz, Andreas Reif, Eva Reininghaus, Sara Richardson, Guy A. Rouleau, Janusz K. Rybakowski, Martin Schalling, Peter R. Schofield, Oliver K. Schubert, Barbara Schweizer, Florian Seemüller, Maria Grigoroiu-Serbanescu, Giovanni Severino, Lisa R. Seymour, Claire Slaney, Jordan W. Smoller, Alessio Squassina, Thomas Stamm, Jo Steele, Pavla Stopkova, Sarah K. Tighe, Alfonso Tortorella, Gustavo Turecki, Naomi R. Wray, Adam Wright, Peter P. Zandi, David Zilles, Michael Bauer, Marcella Rietschel, Francis J. Mcmahon, Thomas G. Schulze, and Martin Alda (2013). Assessment of Response to Lithium Maintenance Treatment in Bipolar Disorder: A Consortium on Lithium Genetics (ConLiGen) Report. PLoS One, 8(6):e65636. DOI:10.1371/journal.pone.0065636.
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Dr. Hsi-Chung Chen
Department of Psychiatry & Center of Sleep Disorders, National Taiwan University Hospital

Professor Po-Hsiu Kuo
Institute of Epidemiology and Preventive Medicine


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