LAUSR

Background Voltage-gated calcium channels have been implicated in schizophrenia aetiology, however little is known about their involvement in antipsychotic treatment response. This study investigated variants within the calcium channel subunit genes for association with antipsychotic treatment response in a first episode schizophrenia cohort. Methods The patient cohort included 103 unrelated South African FES patients (80% South African Coloured, 12% Xhosa and 8% European descent). Treatment response was assessed using the positive and negative syndrome scale (PANSS) over a period of 12 months, with measurements taken biweekly for the first six weeks, and every three months thereafter. Variants within the calcium channel subunit genes (α1, α2δ, β and γ subunits) were mined from available GWAS data produced using the Infinium OmniExpressExome-8 Kit (Illumina, California, USA). In total 1830 variants were identified within 10 CACNA1 genes, four CACNB genes, four CACNA2D genes and eight CACNG genes. Linear mixed-effects models were used to investigate the effect of genetic variants on change in PANSS scores for each domain (positive, negative, general and total) over the twelve-month period, adjusting for age, gender, proportion ancestry, and baseline PANSS scores. Multiple modes of inheritance were considered and the best-fit model was selected for further analysis. Results Twelve regulatory variants were shown to be significantly associated with treatment outcome. Most notably the CACNA1B rs2229949 CC genotype was associated with improved negative symptomology, where the C-allele was predicted to abolish a miRNA-binding site (has-mir-5002-3p), suggesting a possible mechanism of action through which this variant may have an effect. Discussion These results implicate the calcium channel subunits in antipsychotic treatment response and suggest that increased activation of these channels may be explored to enhance or predict antipsychotic treatment outcome.