PII-074 - BIPOLAR DISORDER GWAS IDENTIFIED A SNP SIGNAL IN THE THSD7A GENE THAT IS ASSOCIATED WITH RESPONSE TO VALPROATE AND LAMOTRIGINE.

K. Valle¹, S. Zhao², A. Ho³, B. Coombes³, J. Biernacka³, D. Liu³, M. Frye³, R. Weinshilboum³; ¹University of Missouri-Columbia School of Medicine, ²Mayo Clinic Graduate School of Biomedical Sciences, ³Mayo Clinic.

Background: A Genome-Wide Association Study (GWAS) evaluated the genetic basis for treatment response to valproate and lamotrigine in bipolar disorder (BD) patients. That GWAS detected a THSD7A single nucleotide polymorphism (SNP) signal associated with treatment response to both drugs. THSD7A encodes Thrombospondin Type 1 Domain Containing 7A, a single-pass transmembrane protein with known functions in endothelial cells and podocytes which include angiogenesis, cell migration, and podocyte foot process formation. However, the function of THSD7A protein in neurons remains unclear. We hypothesized that THSD7A may influence neuronal growth and neurite development.

Methods: To test that hypothesis, antisense oligonucleotides (ASOs) derived from double-stranded DNA were used to knock down the THSD7A gene. Sholl analysis was then applied to quantify forebrain neuron (FBN) growth by designating the neuron's soma as the “center”, with intersection points radiating from the soma in a concentric fashion. The number of intersections that neurites cross is measured and used to determine neurite outgrowth.

Results: Following THSD7A knockdown, the Sholl analysis revealed that the number of intersections was lower in the knockdowns than in the control neurons. Furthermore, the total neuronal surface area, measured with the tubulin marker Tuj1, was significantly decreased in knockdowns compared to controls.

Conclusion: In summary, our experiments showed that THSD7A may influence neurite development and outgrowth. Therefore, SNPs in this gene may influence the clinical phenotype of patients with bipolar disorder and their response to BD drug treatment by affecting normal neurite development. Future experiments should—among other studies—examine protein-protein interactions of the THSD7A protein in neurons.