Lithium, an effective mood stabilizer, is considered the first-line treatment for bipolar disorder in many countries. However, treatment response varies among patients, and only one-third of patients are highly responsive to lithium treatment. Although lithium response is a heritable trait, no genetic markers of treatment response have been reproducibly identified previously. The International Consortium on Lithium Genetics (ConLiGen) was thus formed in 2008, initiated by Thomas G. Schulze and Francis J. McMahon, two outstanding researchers in Germany and NIMH, USA, respectively. The main emphasis of this consortium is to identify important genetic variants that are responsible for inter-individual differences in treatment response, a goal towards precision medicine for patients with bipolar disorder. Among the 22 participating sites across four Continents, one study site contributed on this effort is led by Dr. Po-Hsiu Kuo, associate professor at College of Public Health, National Taiwan University.
With more than six million of single nucleotide polymorphisms (SNPs) data in 2563 patients, the researchers of the consortium reported few SNPs in Chromosome 21 that showed significant associations with lithium responsiveness at the level of p-value=10−9. The associated locus has been annotated with two lncRNA (long non-coding RNA) genes, which are potential regulators of gene expression, particularly in the CNS. These results are published in Lancet in March, 2016. “This finding could have important implications for our understanding of lithium’s mechanism of action in bipolar disorder, although replication in independent samples is needed”, said Dr. Liping Hou of NIMH, the first author of this paper.
The effect of associated locus was further supported by an independent, prospective study of 73 patients treated with lithium monotherapy for a period of up to two years. Significantly lower rate of relapse was observed in carriers of the response-associated alleles (p=0·03, hazard ratio 3·8, 95% CI 1·1–13·0). In addition, an ongoing study of blood gene expression conducted by Dr. Po-Hsiu Kuo, comparing patients with bipolar disorder in acute episode versus partial remission found differential gene expression of one of the lncRNAs identified within the association region (AL157359.3; p=0·08, fold change=1·17). Dr. Hou addressed that “Clinical utility is a high bar, but the current dearth of good biomarkers of lithium response means that any robust genetic markers could constitute a real step forward.”
With more efforts put into the field to perform pharmacogenomics study, as well as experimental work to establish the biological functions of identified loci, we anticipate to having confirmed biomarkers of lithium response in the near future for the development of clinical utility of these findings.