LAUSR

Background Variants of the Calcium Voltage-Gated Channel Subunit Alpha 1 C (CACNA1C) gene have been associated with several neuropsychiatric disorders, most notably Bipolar Disorder (BD) (Cross Disorder Group of PGC., 2013). Previous studies of the function of BD-associated CACNA1C SNPs have tended to study single SNPs in isolation within relatively small samples (Bigos et al., 2010). Circadian rhythm disruption is recognised as a core clinical feature of BD, with BD individuals commonly reporting an evening chronotype preference (Bellivier et al., 2015). Given that CACNA1C has a key role in the regulation of circadian rhythms (Shi et al., 2008), we hypothesised that a CACNA1C Genetic Risk Score (GRS) would be associated both with mood disorder phenotypes and chronotype preference within 95,073 UK Biobank participants. Methods A Genetic Risk Score (GRS) combining several BD-associated CACNA1C SNPs was used to investigate the association between CACNA1C, several mood disorder-related phenotypes (mood instability, neuroticism, BD status, MDD status) and chronotype. In light of evidence of a potential sex-specific effect of CACNA1C variants, secondary analyses were stratified by sex (Dao et al., 2010; Heilbronner et al., 2015). Results There was no association between CACNA1C GRS and any of the mood disorder phenotypes, or chronotype, after adjusting for confounding factors (age, sex, social deprivation and genetic principal components). However, there was preliminary evidence of an association between higher CACNA1C GRS score and BD status in females (p=0.03). Discussion Overall, we did not find association between CACNA1C GRS and a range of mood disorder phenotypes or chronotype preference within the UK Biobank cohort, but there was evidence of a potential sex-specific effect of CACNA1C variants on BD status in females. There is currently considerable interest in the repurposing of calcium channel blockers (CBBs) as new treatments for BD (Keers et al., 2009). Our findings, which require replication in other cohorts, suggest that there may be a sex difference in therapeutic effect of CCBs used to treat BD.