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

BACKGROUND: Lithium remains 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 have been reproducibly identified. METHODS: Here we report the results of a genome-wide association study of lithium response in 2,563 patients collected by 22 participating sites from the International Consortium on Lithium Genetics (ConLiGen); the largest attempted so far. Data from over 6 million common single nucleotide polymorphisms (SNPs) were tested for association with categorical and continuous ratings of lithium response of known reliability. 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); rs75222709: p=3·50×10(−9)). In an independent, prospective study of 73 patients treated with lithium monotherapy for a period of up to two years, carriers of the response-associated alleles had a significantly lower rate of relapse than carriers of the alternate alleles (p=0·03, hazard ratio = 3·8). INTERPRETATION: The response-associated region contains two genes coding 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. Further studies are needed to establish the biological context of these findings and their potential clinical utility. Confirmed biomarkers of lithium response would constitute an important step forward in the clinical management of bipolar disorder.