UCLA

Bipolar disorder (BD) is a highly heritable mood disorder with a complex genetic architecture. It is commonly treated prophylactically with the mood stabilizer lithium, although treatment responses vary widely across patients. Both how BD genetic variants confer risk and the molecular mechanisms underlying lithium’s therapeutic effects remain poorly understood. This dissertation begins with a review of recent findings from BD and lithium-response genetic studies and from BD and lithium treatment transcriptomic studies. This review will show that while presenting an opportunity to learn valuable information about underlying biology, gene expression studies investigating these phenotypes have had low sample sizes and inconsistent findings. Then, an original study attempting to fill this gap by exploring the whole blood transcriptome in a large BD case-control RNA sequencing sample is reported on. In this study, strong effects of lithium treatment and cell-type composition were revealed, pointing to potential therapeutic mechanisms of lithium, and underlining the importance of carefully correcting for these variables. To put these findings in the context of the current understanding of BD etiology and lithium treatment mechanisms, a comparison was made with findings previously reported highlighting a list of high-confidence lithium-associated genes. A gene-set analysis comparing genes with differential expression to genes implicated from major psychiatric genome-wide association studies revealed that the observed gene expression changes were unrelated to genetic risk. The findings herein contribute to the current understanding of the BD transcriptome in whole blood and provide evidence for the mechanistic actions of lithium treatment.