Genetic Variants Predict Lithium Response in Bipolar Disorder

Genetic variations on a stretch of chromosome may predict responsiveness among patients with bipolar disorder to the mood stabilizing drug lithium (multiple brands), a genome-wide analysis by an international consortium shows.

The study, led by Francis J. McMahon, MD, National Institute of Mental Health, Bethesda, Maryland, showed that four single-nucleotide polymorphisms (SNPs) on chromosome 21 were linked to lithium response. A separate analysis indicated that carriers have an almost fourfold reduction in relapse rates.

Although lithium is a first-line treatment for bipolar disorder, previous studies have indicated that individual patient responses are variable, with at least 30% of patients having no clinical response.

“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,” the team says.

They add: “Personal treatment planning on the basis of genetic data depends on identification of additional markers and their total contribution to differences between individuals in response to treatment. Detection of genome-wide significant markers for a phenotype is the first step in demonstrating if such a goal is achievable.”

The research was published online January 26 in the Lancet.

“A Real Step Forward”

For the study, investigators examined 2563 bipolar disorder patients from 22 sites in Europe, America, Asia, and Australia that are participating in the International Consortium on Lithium Genetics.

They conducted a genome-wide association study in which data on common SNPs at more than six million sites were analyzed for associations with categorical and continuous ratings of lithium responses on the Alda scale.

The analyses were conducted in two batches, and the results were combined using meta-analysis techniques. These showed that a single locus of four linked SNPs on chromosome 21 met the criteria for association with lithium response: rs79663003, rs78015114, rs74795342, and rs75222709.

This region contains two genes for long, noncoding RNAs (lncRNAs) that have roles in regulating gene expression and other cell processes. For example, the authors note a recent study that found that expression of one of the lncRNAs that was identified in the association region was reduced in patients with bipolar disorder following a manic episode.

To verify the results, the researchers conducted an independent, prospective analysis of 73 patients with bipolar disorder who underwent lithium monotherapy for up to 2 years.

They found that, following correction for several factors known to affect relapse, carriers of the SNPs had significantly lower rates of disease relapse than carriers of the alternate alleles (hazard ratio, 3.8; P = .03368).

The team concedes, however, that the clinical utility of these findings may be “limited.”

“[A]dditional genetic markers from future studies could ultimately lead to a clinically informative test, but additional information from established predictors such as family history might be needed, as has been observed for other phenotypes…. 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,” they write.

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