Genome-wide association study of response to lithium treatment in bipolar disorder using the international Consortium on Lithium Genetics sample
Final Report Abstract
Lithium is widely used in psychiatry. In Bipolar Disorder (BD), lithium acts as a mood stabilizer, preventing illness-induced episodes of mania and depression. Despite well-documented beneficial effects, only approximately one third of BD patients respond adequately to lithium treatment. Previous research has shown this treatment response to be familial. Similar to BD itself, response to lithium thus appears to be chiefly mediated by genetic factors. However, it remains unclear which molecular targets underlie this differential treatment responsiveness. Most previous studies have suffered from two drawbacks: 1) small sample sizes, leading to diminished statistical power and 2) different methods used to assess lithium responsiveness, often lacking psychometric standards. The present grant aimed to address these problems by establishing the ConLiGen Consortium, which aims at conducting well-powered molecular studies of lithium responsiveness in BD. Two milestones have been accomplished so far. Firstly, an international inter-rater reliability study has been conducted, identifying the optimal way in which response to lithium can be assessed in terms of psychometry. Secondly, a genome-wide association study (GWAS) has been conducted in more than 3,000 participants from Europe, North America, Australia and Asia, using results from the inter-rater reliability study to optimize the way the lithium response phenotype is captured. First results of this study show lithium responsiveness to be associated with variations of four single-nucleotide polymorphisms (SNPs) in the gene AL157359.4 on chromosome 21. This DNA region is transcribed to long intergenic non-coding RNA (lincRNA). The functional roles of lincRNAs are largely unknown. Results from the GWAS are currently being validated in independent samples of lithium-treated BD patients. Many further studies will be conducted in this unique sample. In the future, results might be used to establish a diagnostic test for lithium responsiveness in BD.
Publications
- (2010). The International Consortium on Lithium Genetics (ConLiGen): An Initiative by the NIMH and IGSLI to Study the Genetic Basis of Response to Lithium Treatment. Neuropsychobiology. 62(1):72-8
Schulze, T.G., ..., Bauer, M., and McMahon, F.J.
- (2012). An update from the Consortium on Lithium Genetics (ConLiGen): Phenomic and Genomic studies. 26th meeting of the International Group for the Study of Lithium Treated Patients (IGSLI) in Berlin, Germany
Heilbronner, U.
- (2013). Assessment of response to lithium maintenance treatment in bipolar disorder: a Consortium on Lithium Genetics (ConLiGen) report. PLOS ONE 8, e65636
Manchia, M., ..., Bauer, M., Rietschel, M., McMahon, F.J., Schulze, T.G., and Alda, M.
(See online at https://doi.org/10.1371/journal.pone.0065636) - (2014) Genome-wide association Study reveals two new risk loci for bipolar disorder. Nature Communications, 5:3339
Mühleisen, T.W., Leber, M., Schulze, T.G., Strohmaier, J., Degenhardt, F., Treutlein, J., Mattheisen, M., Forstner, A.j., Schumacher, J., Breuer, R., Meier, S., Herms, S., Hoffmann, P., Lacour, A., Witt, S.H., Reif, A., Müller-Myshok, B., Lucae, S., Maier, W., Schwarz, M., Vedder, H., Kammerer-Ciernioch, J., Pfennig, A., Bauer, M., Hautzinger, M., Moebus, S., Priebe, L., Czerski, P.M., Hauser, J., Lissowska, J., Szeszenia-Dabrowska, N., Brennan, P., McKay, J.D., Wright, A., Mitchell, P.B., Fullerton, J.M., Schofield, P.R. Montgomery, G.W., Medland, S.E., Gordon, S.D., Martin, N.G., Krasnow, V., Chuchalin, A., Babadjanova, G., Pantelejeva, G., Abramova, L.I., Tiganov, A.S., Polonikov, A., Khusnutdinova, E., Alda, M., Grof, P., Rouleau, G.A., Turecki, G., Laprise, C., Rivas, F., Mayoral, F., Kogevinas, M., Grigoroiu-Serbanescu, M., Propping, P., Becker, T., Rietschel, M., Nöthen, M.M., Cichon, S.
(See online at https://doi.org/10.1038/ncomms4339) - (2014). An update from the Consortium on Lithium Genetics (ConLiGen): Phenomic and Genomic studies. XXIInd World Congress of Psychiatric Genetics in Copenhagen, Denmark
Heilbronner, U.
(See online at https://doi.org/10.1016/j.comppsych.2014.08.019) - (2014). ConLiGen - a consortium investigating the genetic underpinnings of lithium response in bipolar disorder. Annales Médico-Psychologiques, Revue Psychiatrique. 172:197–198
Heilbronner, U. and Schulze, T.G.S.
(See online at https://doi.org/10.1016/j.amp.2014.02.017) - No association between GADL1 markers and lithium response in asians with bipolar disorder. The New England Journal of Medicine. 370(19):1857-9
Hou, L., Heilbronner, U., Rietschel, M., Kato, T., Kuo, P.-H., McMahon, F.J. and Schulze, T.G.
- (2015) Test-retest reliability of a new questionnaire for the retrospective assessment of long-term lithium use in bipolar disorder. Journal of Affective Disorders. 174: 589-593
Tighe, S.K., Ritchey, M., Schweizer, B., Goes, F.S., MacKinnon, D., Mondimore, F., DePaulo, J.R., McMahon, F.J., Schulze, T.G., Zandi, P.P., Potash, J.B.
(See online at https://doi.org/10.1016/j.jad.2014.11.021)
