M21 - VARIANTS IN THE PROMOTER OF TRKB ARE ASSOCIATED WITH A GOOD RESPONSE TO LITHIUM IN BIPOLAR DISORDER

Abstract

Background BDNF and its receptor TrkB have repeatedly been associated with bipolar disorder and lithium response. Lithium induces release of BDNF which is essential for its function. We have previously shown that genetic variants in the TrkB gene are associated with lithium response and bipolar disorder. The goal of this study was to identify novel and common sequence variants in these two genes that affect the action of lithium in bipolar disorder. Methods Retrospective samples were collected in regard to lithium responsiveness. 73 good responders, (LiR), 49 moderate responders (Mod), and 47 poor responders (NR) individuals were used for a sequencing study of these two genes. We targeted exons, non-coding regions with putative regulatory functions, 5’ and 3’ untranslated regions, and numerous DNase hypersensitive regions. Samples were combined into pools of 23 to 37 individuals. Paired-end sequencing was done using Custom Amplicons (Illumina). Variants were called with Genome Analysis Toolkit. PLINK was used to calculate a chi-square statistic between individual groups. Annotation of identified variants was done using SIFT and PolyPhen-2. Results For BDNF, 35 variants were called, and 159 variants were called for TrkB. Using a conservative Bonferroni correction for 174 comparisons, a statistically significant p-value would be Discussion Targeted sequencing revealed the over abundance of a minor allele of a common SNP in the promoter of TrkB for LiR but not in NR. Lithium efficacy for the treatment of bipolar disorder is likely to involve the BDNF/TrkB pathway. This study provides a likely candidate region to further investigate the function of lithium in bipolar individuals.