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

Article


Tecelão, Diogo, Mendes, Ana, Martins, Daniel, Fu, C., Chaddock, Christopher A, Picchioni, Marco M, McDonald, Colm, Kalidindi, Sridevi, Murray, Robin and Prata, Diana P 2018. The effect of psychosis associated CACNA1C, and its epistasis with ZNF804A, on brain function. Genes, Brain and Behavior. 18 (4), p. e12510.
AuthorsTecelão, Diogo, Mendes, Ana, Martins, Daniel, Fu, C., Chaddock, Christopher A, Picchioni, Marco M, McDonald, Colm, Kalidindi, Sridevi, Murray, Robin and Prata, Diana P
Abstract

CACNA1C‐rs1006737 and ZNF804A‐rs1344706 polymorphisms are amongst 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.

JournalGenes, Brain and Behavior
Journal citation18 (4), p. e12510
ISSN1601-1848
Year2018
PublisherWiley
Accepted author manuscript
License
Digital Object Identifier (DOI)doi:10.1111/gbb.12510
Web address (URL)https://doi.org/10.1111/gbb.12510
Publication dates
Online05 Aug 2018
Publication process dates
Deposited08 Aug 2018
Accepted02 Aug 2018
Accepted02 Aug 2018
FunderNational Institute for Health Research
Marie Curie Career Integration
Fundação para Ciência e Tecnologia
Fundação para Ciência e Tecnologia
Fundação para Ciência e Tecnologia
AstraZeneca and the Faculty of Medicine of the University of Lisbon
Medical Research Council
Wellcome Trust
British Research Council
Copyright information© 2018 Wiley. This is the peer reviewed version of the following article: Tecelão, D. et al. 'The effect of psychosis associated CACNA1C, and its epistasis with ZNF804A, on brain function', Genes, Brain and Behavior, 18 (4) e12510, which has been published in final form at: https://doi.org/10.1111/gbb.12510. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions
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