Mood-Stabilizing Antiepileptic Treatment Response In Bipolar Disorder: A Genome-Wide Association Study

Several antiepileptic drugs (AEDs) have US Food and Drug Administration (FDA) approval for use as mood stabilizers in bipolar disorder (BD), but not all BD patients respond to these AED mood stabilizers (AED-MSs). To identify genetic polymorphisms that contribute to the variability in AED-MS response, we performed a discovery genome-wide association study (GWAS) of 199 BD patients from the Mayo Clinic Bipolar Disorder Biobank. Most of these patients had been treated with the AED-MS valproate/divalproex and/or lamotrigine. AED-MS response was assessed using the Alda scale, which quantifies clinical improvement while accounting for potential confounding factors. We identified two genome-wide significant single-nucleotide polymorphism (SNP) signals that mapped to theTHSD7A(rs78835388,P = 7.1E-09) andSLC35F3(rs114872993,P = 3.2E-08) genes. We also identified two genes with statistically significant gene-level associations:ABCC1(P = 6.7E-07; top SNP rs875740,P = 2.0E-6), andDISP1(P = 8.9E-07; top SNP rs34701716,P = 8.9E-07).THSD7ASNPs were previously found to be associated with risk for several psychiatric disorders, including BD. BothTHSD7AandSLC35F3are expressed in excitatory/glutamatergic and inhibitory/gamma-aminobutyric acidergic (GABAergic) neurons, which are targets of AED-MSs.ABCC1is involved in the transport of valproate and lamotrigine metabolites, and the SNPs inABCC1andDISP1with the strongest evidence of association in our GWAS are strong splicing quantitative trait loci in the human gut, suggesting a possible influence on drug absorption. In conclusion, our pharmacogenomic study identified novel genetic loci that appear to contribute to AED-MS treatment response, and may facilitate precision medicine in BD.