Abstract
BACKGROUND: Responsiveness to mood-stabilizing pharmacotherapy varies in bipolar disorder (BD). We investigated clinical correlates of second-generation antipsychotic (SGA) treatment response and conducted the first genome-wide association study (GWAS), including exploratory polygenic scores (PGS), of SGA pharmacogenomic treatment response in BD. METHODS: Treatment response was quantified using the Alda scale, and GWAS was performed using Alda-A score, controlling for sex, genotyping batch, and the genomic principal components. RESULTS: The cohort included 2,159 adults with BD (1,416 BD-I, 691 BD-II, 51 schizoaffective BD), mean age 41.8 years, 62% female, 84% white, and 14% Hispanic. Nearly half (48%) were treated with SGAs. Current SGA users were younger (41.2 ± 14.7 vs. 42.5 ± 15.3 years, p = 0.040), more likely to be Hispanic (14% vs. 11%, p = 0.047), had a higher body mass index (BMI; 30.4 ± 7.6 vs. 29.5 ± 7.1 kg/m(2), p = 0.005). Lifetime comorbidity patterns for current SGA users include higher rates of manic psychosis (29% vs. 17%, p < 0.001) and eating disorders - Anorexia Nervosa (7% vs. 4%, p = 0.003), Bulimia Nervosa (7% vs. 4%, p = 0.003), and Binge Eating Disorder (14% vs. 11%, p = 0.030). We detected a genome-wide significant association between SGA Alda-A scores and GAS7 variants (top variant: rs202127418, β=-2.998, p = 4.96E-08). However, SGA response was not significantly associated with PGS for schizophrenia, BD, and major depression (FDR > 0.05). CONCLUSIONS: SGAs are frequently utilized as mood stabilizers in patients with BD and are associated with manic psychosis and eating disorders. GAS7 variants may predict SGA response, but larger, more diverse cohorts are needed for validation.