The effect of psychosis associated CACNA1C, and its epistasis with ZNF804A, on brain function

Abstract

CACNA1C-rs1006737 and ZNF804A-rs1344706 polymorphisms are among the most robustly associated with schizophrenia (SCZ) and bipolar disorder (BD), and recently with brain phenotypes. As these patients show abnormal verbal fluency (VF) and related brain activation, we asked whether the latter was affected by these polymorphisms (alone and in interaction)-to better understand how they might induce risk. We recently reported effects on functional VF-related (for ZNF804A-rs1344706) and structural (for both) connectivity. We genotyped and fMRI-scanned 54 SCZ, 40 BD and 80 controls during VF. With SPM, we assessed the main effect of CACNA1C-rs1006737, and its interaction with ZNF804A-rs1344706, and their interaction with diagnosis, on regional brain activation and functional connectivity (psychophysiological interactions-PPI). Using public data, we reported effects of CACNA1C-rs1006737 and diagnosis on brain expression. The CACNA1C-rs1006737 risk allele was associated with increased activation, particularly in the bilateral prefronto-temporal cortex and thalamus; decreased PPI, especially in the left temporal cortex; and gene expression in white matter and the cerebellum. We also found unprecedented evidence for epistasis (interaction between genetic polymorphisms) in the caudate nucleus, thalamus, and cingulate and temporal cortical activation; and CACNA1C up-regulation in SCZ and BD parietal cortices. Some effects were dependent on BD/SCZ diagnosis. All imaging results were whole-brain, voxel-wise, and familywise-error corrected. Our results support evidence implicating CACNA1C and ZNF804A in BD and SCZ, adding novel imaging evidence in clinical populations, and of epistasis-which needs further replication. Further scrutiny of the inherent neurobiological mechanisms may disclose their potential as putative drug targets.

Genetic Analysis of the ZNF804A Gene in Mexican Patients With Schizophrenia, Schizoaffective Disorder and Bipolar Disorder 

“…A bioinformatic study found an interaction between rs1344706 and rs11685645 of Myt1L gene, and between rs1344706 and rs1836796 of NCAM1 gene, concluding that these SNPs may be implicated in the early development of central nervous system (Hess et al 2015;Riley et al 2010). Also, interaction study between rs1344706 and a SNP of CACNA1C reported association with increase activation in brain regions of SCZ and BPD patients (Tecelão et al 2019). In addition, it was reported an interaction effect of rs1344706 and COMT variant on brain activity in healthy individuals (Cui et al 2019).…”

Variable Phenotypes of Epilepsy, Intellectual Disability, and Schizophrenia Caused by 12p13.33–p13.32 Terminal Microdeletion in a Korean Family: A Case Report and Literature Review

“…The CACNA1C gene encodes the alpha-1 subunit of L-type voltage-dependent calcium channel (as known as Cav1.2) that is widely expressed in the brain (predominantly in the hippocampus, thalamus, and cerebral cortex) [ 32 ]. The Cav1.2 channel plays a part in neurotransmitter release, synaptogenesis, and neuronal excitability; therefore, mutation of CACNA1C is a possible cause of neuropsychiatric disorders [ 33 ]. Recently, the CACNA1C haploinsufficiency was reported to be responsible for the common features of interstitial 12p13.33 deletion carriers [ 23 ].…”

“…Furthermore, rs1006737 or the CACNA1C and rs1344706 ZNF804A were commonly associated with schizophrenia and bipolar disorder, and recently with brain phenotypes. For instance, CACNA1C up-regulation in schizophrenia and bipolar disorder parietal cortices [ 33 ] and implication of CACN1C variants in Timothy syndrome, depression, schizophrenia, bipolar disorder, and impairment of working memory and verbal fluency [ 34 , 35 ]. The CACN1C has potential pathogenicity in corresponding epilepsy [ 36 ]; two families with CACNA1C mutation were presented with neonatal epileptic encephalopathy and/or epilepsy combined DD/ID [ 37 ].…”

Shaping the Trans-Scale Properties of Schizophrenia via Cerebral Alterations on Magnetic Resonance Imaging and Single-Nucleotide Polymorphisms of Coding and Non-Coding Regions

“…For the CACNA1C rs1006737, the risk allele carriers (AA/AG) show decreased connectivity between the left precentral gyrus/inferior frontal gyrus and superior temporal gyrus vs. non-risk allele homozygotes (GG) in schizophrenia, thus presenting abnormal verbal fluency (Tecelao et al, 2019 ). ZNF804A rs1344706 seems to play an important role in FC between the left hippocampus and right DLPFC, which may serve as the brain mechanism of rs1344706 in schizophrenia (Zhang et al, 2018 ).…”