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

TitleGenetic variants associated with response to lithium treatment in bipolar disorder: a genome-wide association study.
Publication TypeJournal Article
Year of Publication2016
AuthorsHou L, Heilbronner U, Degenhardt F, Adli M, Akiyama K, Akula N, Ardau R, Arias B, Backlund L, Banzato CEM et al.
JournalLancet
Volume387
Issue10023
Pagination1085-93
Date Published2016 Mar 12
ISSN1474-547X
KeywordsBipolar Disorder, Female, Genetic Variation, Genome-Wide Association Study, Genotype, Glial Cell Line-Derived Neurotrophic Factor Receptors, Humans, Lithium Compounds, Male, Middle Aged, Phenotype, Polymorphism, Single Nucleotide, Prospective Studies, Treatment Outcome
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.

DOI10.1016/S0140-6736(16)00143-4
Alternate JournalLancet
PubMed ID26806518
PubMed Central IDPMC4814312
Grant ListZ99 MH999999 / / Intramural NIH HHS / United States
R01 MH059556 / MH / NIMH NIH HHS / United States
64410 / / Canadian Institutes of Health Research / Canada
R01 MH059535 / MH / NIMH NIH HHS / United States
R01 MH59545 / MH / NIMH NIH HHS / United States
R01 MH059567 / MH / NIMH NIH HHS / United States
R01 MH59533 / MH / NIMH NIH HHS / United States
R01 MH059545 / MH / NIMH NIH HHS / United States
5K02DA021237 / DA / NIDA NIH HHS / United States
P01 CA089392 / CA / NCI NIH HHS / United States
1Z01MH002810-01 / MH / NIMH NIH HHS / United States
K02 DA21237 / DA / NIDA NIH HHS / United States
R01 MH059548 / MH / NIMH NIH HHS / United States
R01 MH059534 / MH / NIMH NIH HHS / United States
R01 MH59535 / MH / NIMH NIH HHS / United States
R01 MH59553 / MH / NIMH NIH HHS / United States
R01 MH60068 / MH / NIMH NIH HHS / United States
R01 MH059533 / MH / NIMH NIH HHS / United States
K02 DA021237 / DA / NIDA NIH HHS / United States
Z01 MH002810 / MH / NIMH NIH HHS / United States
P50CA89392 / CA / NCI NIH HHS / United States
R01 MH59567 / MH / NIMH NIH HHS / United States
R01 MH059553 / MH / NIMH NIH HHS / United States
MR/L006642/1 / / Medical Research Council / United Kingdom
ZIA-MH00284311 / MH / NIMH NIH HHS / United States
R01 MH060068 / MH / NIMH NIH HHS / United States