title: The impact of CACNA1C gene, and its epistasis with ZNF804A, on white matter microstructure in health, schizophrenia and bipolar disorder1.
abstract: Genome-wide studies have identified allele A (adenine) of single nucleotide polymorphism (SNP) rs1006737 of the calcium-channel CACNA1C gene as a risk factor for both schizophrenia (SZ) and bipolar disorder (BD) as well as allele A for rs1344706 in the ZNF804A gene. These illnesses have also been associated with white matter abnormalities, reflected by reductions in fractional anisotropy (FA), measured using diffusion tensor imaging (DTI). We assessed the impact of the CACNA1C psychosis risk variant on FA in SZ, BD and health. 230 individuals (with existing ZNF804A rs1344706 genotype data) were genotyped for CACNA1C rs1006737 and underwent DTI. FA data was analysed with tract-based spatial statistics and threshold-free cluster enhancement significance correction (P < 0.05) to detect effects of CACNA1C genotype on FA, and its potential interaction with ZNF804A genotype and with diagnosis, on FA. There was no significant main effect of the CACNA1C genotype on FA, nor diagnosis by genotype(s) interactions. Nevertheless, when inspecting SZ in particular, risk allele carriers had significantly lower FA than the protective genotype individuals, in portions of the left middle occipital and parahippocampal gyri, right cerebellum, left optic radiation and left inferior and superior temporal gyri. Our data suggests a minor involvement of CACNA1C rs1006737 in psychosis via conferring susceptibility to white matter microstructural abnormalities in SZ. Put in perspective, ZNF804A rs1344706, not only had a significant main effect, but its SZ-specific effects were two orders of magnitude more widespread than that of CACNA1C rs1006737.
authors: Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London.|Computational, Cognitive and Clinical Neuroimaging Laboratory, Division of Brain Sciences, Department of Medicine, Imperial College London, London.
authors: E
authors: E
authors: Mallas
authors: Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London.|Department of Neuroradiology, John Radcliffe Hospital, Oxford University Hospitals NHS Trust, Oxford.
authors: F
authors: F
authors: Carletti
authors: Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London.
authors: C A
authors: CA
authors: Chaddock
authors: Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London.
authors: S
authors: S
authors: Shergill
authors: Psychological Medicine, Royal Brompton & Harefield NHS Trust, London.
authors: J
authors: J
authors: Woolley
authors: Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London.|St. Andrew's Academic Department, St Andrew's Healthcare, Northampton, UK.
authors: M M
authors: MM
authors: Picchioni
authors: Neuroimaging, Cognition & Genomics Centre (NICOG) & NCBES Galway Neuroscience Centre, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland.
authors: C
authors: C
authors: McDonald
authors: Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London.|Department of Psychology, The University of Hong Kong, Hong Kong Special Administrative Region.
authors: T
authors: T
authors: Toulopoulou
authors: Department of Psychology, Institute of Psychiatry, Psychology & Neuroscience King's College London.
authors: E
authors: E
authors: Kravariti
authors: Department of Psychology, Institute of Psychiatry, Psychology & Neuroscience King's College London.
authors: S
authors: S
authors: Kalidindi
authors: Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London.|Mental Health Neurosciences Research Department, Division of Psychiatry, University College London.
authors: E
authors: E
authors: Bramon
authors: Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London.
authors: R
authors: R
authors: Murray
authors: Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
authors: G J
authors: GJ
authors: Barker
authors: Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.|Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal.
authors: D P
authors: DP
authors: Prata
mesh_terms: D000328:Adult; D000483:Alleles; D001714:Bipolar Disorder / Q000235:genetics / Q000503:physiopathology; D020746:Calcium Channels, L-Type / Q000235:genetics* / Q000378:metabolism; D056324:Diffusion Tensor Imaging; D004843:Epistasis, Genetic; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011618:Psychotic Disorders / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics / Q000503:physiopathology; D066127:White Matter / Q000378:metabolism / Q000502:physiology* / Q000648:ultrastructure
chemical_list: C079146:CACNA1C protein, human; D020746:Calcium Channels, L-Type; D051741:Kruppel-Like Transcription Factors; C540527:ZNF804A protein, human
keywords: 
  CACNA1C
  ; Bipolar disorder; ZNF804A epistasis; diffusion tensor imaging; fractional anisotropy; genome-wide association; rs1006737; schizophrenia; white matter