CACNA1C
A case study of genetic risk factors for neuropschiatric disorders
The CACNA1C locus represents a top locus associated with multiple neuropsychiatric disorders. Image credits: Ferreira et al, Nat Gen 2008 and Pardiñas et al Nat Gen 2018.
A top genome-wide association study (GWAS) signal for schizophrenia, bipolar disorder, and major depression lies deep within the ~330-kb third intron of the ~600-kb CACNA1C gene. CACNA1C encodes the pore-forming subunit of CaV1.2, the predominant L-type voltage-gated calcium channel expressed in human brain neurons. CaV1.2 channels on the postsynaptic membrane play a dominant role in triggering a signaling cascade that culminates in nuclear activation, which is important for learning and memory across the evolutionary tree. This locus overlaps an expression quantitative trait locus (eQTL) mapped in the GTEx project and harbors a human-specific variable-number tandem repeat (VNTR) that is peppered with DNase I cleavage. But it remains a mystery how these elements might act individually or together to increase risk for psychiatric disorders.
We have characterized the genetic diversity of the CACNA1C VNTR and fine-mapped its association to psychiatric diseases (Moya et al., medRxiv. 2024). Results of this investigation inform our experimental approach, using Big DNA technology, to humanize the mouse Cacna1c intron 3 in order to dissect the impact of risk and protective variants at the levels of gene transcription, electrophysiology, and mouse behavior.
IN COLLABORATION WITH:
Richard Tsien, Neuroscience Institute at NYU Langone Health