LAUSR

Background Lithium was the first mood stabilizing medication and remains the most effective. A variety of data argue that lithium responsive bipolar disorder may be genetically distinct and hence lithium response may be a powerful probe distinguishing different forms of illness. The Pharmacogenomics of Bipolar Disorder study has recently completed a prospective trial of lithium in order to quantify lithium response in 585 subjects with bipolar I disorder and conducted a GWAS on this sample. We have also recently reported that iPS derived glutamatergic hippocampal neurons demonstrated a 4 fold higher spontaneous firing rate that was reversed by lithium, but only in cells from lithium responders. Realizing that it was very difficult to obtain GWAS-size samples from a prospective trial, the PGBD study was originally designed to use functional data from stem cell derived neurons in order to reduce the number of statistical tests. Methods 11 sites participated in a 2.5 year prospective trial of lithium in bipolar I subjects. After written informed consent and 4 months of stabilization, subjects were followed for 2 years on monotherapy. Response was quantified as time to relapse. 585 subjects were genotyped using the Illumina PsychArray. A pilot GWAS of 321 European American subjects was conducted using plink and principal components from ancestry markers. RNAseq was conducted on all the iPS experiments in which lithium or control was applied to hyperexcitable cells. Expression was analyzed and compared using EdgeR in the Bioconductor package. Results Genes were selected from the iPS RNAseq data that underwent a significant change in expression in response to lithium, but only in cells from lithium responders. This yielded a list of 469 genes which were then compared with brain eQTL databases. 143 of these genes had known variants affecting expression in brain. Of these 143 SNPs, 27 were directly genotyped. The GWAS p values for these 27 SNPs were examined and one SNP was identified (rs621071) on chromosome 1 that regulates a gene on chromosome 9 (CBARP) and a gene on chromosome 19 (CARD19). This SNP showed significant association to lithium response after Bonferroni correction for the much smaller number of tests (p=0.026). Discussion The combined analysis of GWAS and functional studies make possible genomewide analyses of smaller more difficult to phenotype samples. CBARP is a very interesting candidate that binds to CACNA1C and modulates current through L-type voltage gated calcium channels as have been implicated in bipolar disorder. The function of CARD19 is less clear but may involve inhibition of Bcl-10. Lastly, these results suggest that drug response may be a powerful phenotype with which to dissect different cellular mechanisms in bipolar disorder.