Genome-Wide Study Yields Markers of Lithium Response
• Science Update
An international consortium of scientists has identified a stretch of chromosome that is associated with responsiveness to the mood-stabilizing medication lithium among patients with bipolar disorder. While the finding won’t have an immediate clinical application, it is a groundbreaking demonstration of the potential for identifying genetic information that can be used to inform personalized treatment decisions, even in genetically complex disorders. The genes identified are also an avenue for understanding the biology of the lithium response.
People with bipolar disorder experience marked, often extreme shifts in mood and energy. The disorder affects an estimated 2.6 percent of Americans. The mood swings can severely disrupt a person’s ability to function normally; as many as 15 percent of those affected die by suicide. Lithium is a mood stabilizing medication that is a mainstay of treatment. For some patients, it is very effective, virtually eliminating the symptoms. However, about a third of patients respond incompletely, and another third not at all.
NIMH scientist Francis J. McMahon, M.D., and Thomas G. Schulze, M.D., a former NIMH fellow now at the Ludwig-Maximilians-University of Munich, Germany, led a collaboration involving 22 sites participating in the International Consortium on Lithium Genetics to conduct a genome-wide association study (GWAS) in 2563 patients with bipolar disorder. Like all psychiatric disorders, bipolar disorder is genetically complex; it is likely that many genes, with small effects individually, influence the risk of developing it. In addition, risk genes interact with environmental factors to cause the disorder, making the search for risk genes that much more difficult. These challenges mean that large numbers of patients are necessary to enable scientists to detect associations between gene regions and biological effects.
Scientists in this study scanned genomes of participating patients, testing whether any of 6 million single nucleotide polymorphisms (SNPs), pinpoint variations in DNA across the genome, were associated with a person’s response to lithium. Four SNPs in a single location on chromosome 21 met criteria for association. The region identified contains two genes for long, non-coding RNAs (lncRNAs). In addition to RNA’s role as an intermediary in the translation of genes into proteins, it is now known to have a broader variety of biologic roles, including regulating such functions as gene expression and other cell processes. The identification of these lncRNAs offers scientists targets with which to explore how these molecules shape how someone responds to lithium.
While the patient population in this study was larger than any previous focused on the genetics of the lithium response, like other GWAS studies, this one depended on patients’ recall of their treatment experience. In an effort to test these results in a way that would avoid the uncertainties of recall, the scientific team also looked for these SNPs in a separate, smaller group of (89) patients who were being treated with lithium and assessed prospectively, or as their treatment continued. The SNPs were indeed associated with poorer lithium response, adding confidence to the original finding.
The need for “biomarkers” of lithium response—and for treatment effectiveness over the range of psychiatric disorders—is great. For genetic information to be useful in the clinic for guiding treatment choices for individuals, it may be necessary to have information on a large number of genes in addition to other types of information on individuals. The identification of genetic markers is one facet of the effort to move health care towards precision medicine , an approach in which disease treatment and prevention takes into account individual variability in genes, environment, and lifestyle. The results reported here will require replication, but this study suggests that ongoing research can provide information on genes that will be of use in health care, even for disorders in which the genetics are complex, and the effects of individual genes subtle.
ZIA-MH00284311 (NIMH Intramural Research Program), CA89392, DA021237. Other NIH grants supported data and biomaterial collected in the NIMH Bipolar Disorder Genetics Initiative.
Hou L et al. Genetic variants associated with response to lithium treatment in bipolar disorder: a genome-wide association study. Lancet 2016. Published online January 21, 2016 doi:10.1016/S0140-6736(16)00143-4 .
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