Evidence for cis-acting regulation of ANK3 and CACNA1C gene expression

Objectives: Genome-wide association studies (GWAS) have identified Ankyrin-G (ANK3) and the α-1C subunit of the L-type voltage-gated calcium channel (CACNA1C) as susceptibility genes for bipolar disorder. Available biological information on these genes suggests a potential molecular mechanism involving ion channel dysfunction. The associated single nucleotide polymorphisms (SNPs) at ANK3 (rs10994336) and CACNA1C (rs1006737) are both intronic with no obvious impact on gene function. We investigated whether, instead of affecting protein function, these risk variants might impact on gene regulation affecting expression. Methods: We have done this by testing for allelic expression imbalance (AEI) to identify cis-acting regulatory polymorphisms. Results: We identified evidence of cis-acting variation at both loci in HapMap Caucasian Europeans from Utah (CEU) lymphoblastoid cell lines. There was considerable evidence of AEI at ANK3 with more than half of all heterozygous samples (21 out of 34) for marker SNP rs3750800 showing AEI and a small number of samples showing near monoallelic expression. The AEI at either gene could not be attributed to the GWAS-associated SNPs. Conclusions: These data indicate that there is genetic variation local to both genes affecting their expression, but that this variation is not responsible for increasing risk of bipolar disorder.