Whole genome pharmacogenomic analysis of bipolar disease patients under lithium treatment

Abstract

Bipolar Disorder (BD) is a lifelong psychiatric disease characterized by manic and depressive episodes affecting 1-5% of the general population. Among the most effective mood-stabilizing treatments, lithium (Li) represents the mainstay in the therapeutic management of acute-mania and depression in BD and is still to date, the first choice pro-phylactic treatment. Besides the high rate of excellent Li responders (~30-40%), a significant fraction of patients present patterns of partial or non response to prophylactic treatment with Li. It has been shown that the variability in Li response is strongly influenced by genetic determinants. A large number of studies have investigated the role of genes in modulating the response to Li reporting contrasting findings. In our study, we have genotyped 50 individuals divided in two groups, according to their degree of Li response. The eleven-point treatment response scale we employed (full response cut-off ≥7) allowed us to classify 25 BD patients as non-responders (scored with 0) and 25 as full responders (scored with 8 or higher). These patients were genotyped using the Affymetrix Array 6.0 SNP microarrays (Santa Clara, CA, USA). Data were statistically evaluated using the Genespring software using a p-value cut off of 0.01. We have identified 38 SNPs significantly associated with Li response, with p-values ranging from 1x10-5 to 4x10-6. The genomic loci hold genes encoding for elements of G-proteins coupled receptors, LIM-domain binding proteins, sodium channels and GABA receptors. This study enriches the battery of genetic biomarkers that would personalize Li treatment of BD patients.