title: Genome-wide discovered psychosis-risk gene ZNF804A impacts on white matter microstructure in health, schizophrenia and bipolar disorder.
abstract: Background. Schizophrenia (SZ) and bipolar disorder (BD) have both been associated with reduced microstructural white matter integrity using, as a proxy, fractional anisotropy (FA) detected using diffusion tensor imaging (DTI). Genetic susceptibility for both illnesses has also been positively correlated in recent genome-wide association studies with allele A (adenine) of single nucleotide polymorphism (SNP) rs1344706 of the ZNF804A gene. However, little is known about how the genomic linkage disequilibrium region tagged by this SNP impacts on the brain to increase risk for psychosis. This study aimed to assess the impact of this risk variant on FA in patients with SZ, in those with BD and in healthy controls. Methods. 230 individuals were genotyped for the rs1344706 SNP and underwent DTI. We used tract-based spatial statistics (TBSS) followed by an analysis of variance, with threshold-free cluster enhancement (TFCE), to assess underlying effects of genotype, diagnosis and their interaction, on FA. Results. As predicted, statistically significant reductions in FA across a widely distributed brain network (p < 0.05, TFCE-corrected) were positively associated both with a diagnosis of SZ or BD and with the double (homozygous) presence of the ZNF804A rs1344706 risk variant (A). The main effect of genotype was medium (d = 0.48 in a 44,054-voxel cluster) and the effect in the SZ group alone was large (d = 1.01 in a 51,260-voxel cluster), with no significant effects in BD or controls, in isolation. No areas under a significant diagnosis by genotype interaction were found. Discussion. We provide the first evidence in a predominantly Caucasian clinical sample, of an association between ZNF804A rs1344706 A-homozygosity and reduced FA, both irrespective of diagnosis and particularly in SZ (in overlapping brain areas). This suggests that the previously observed involvement of this genomic region in psychosis susceptibility, and in impaired functional connectivity, may be conferred through it inducing abnormalities in white matter microstructure.
authors.affiliation: Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, University of London, London, United Kingdom; Computational, Cognitive and Clinical Neuroimaging Laboratory, Division of Brain Sciences, Department of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Emma-Jane
authors.initials: EJ
authors.lastname: Mallas
authors.affiliation: Department of Neuroradiology, John Radcliffe Hospital, Oxford University Hospitals NHS Trust , Oxford , United Kingdom.
authors.forename: Francesco
authors.initials: F
authors.lastname: Carletti
authors.affiliation: Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, University of London , London , United Kingdom.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Chaddock
authors.affiliation: Psychological Medicine, Royal Brompton & Harefield NHS Trust , London , United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Woolley
authors.affiliation: Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, University of London, London, United Kingdom; St Andrew's Academic Department, St Andrew's Healthcare, Northampton, United Kingdom.
authors.forename: Marco M
authors.initials: MM
authors.lastname: Picchioni
authors.affiliation: Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, University of London , London , United Kingdom.
authors.forename: Sukhwinder S
authors.initials: SS
authors.lastname: Shergill
authors.affiliation: Department of Psychology, Institute of Psychiatry, Psychology and Neuroscience, King's College London, University of London , London , United Kingdom.
authors.forename: Fergus
authors.initials: F
authors.lastname: Kane
authors.affiliation: Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, University of London , London , United Kingdom.
authors.forename: Matthew P G
authors.initials: MP
authors.lastname: Allin
authors.affiliation: Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King's College London, University of London , London , United Kingdom.
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Barker
authors.affiliation: Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King's College London, University of London, London, United Kingdom; Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
authors.forename: Diana P
authors.initials: DP
authors.lastname: Prata
keywords: Bipolar disorder; Diffusion tensor imaging; Fractional anisotropy; Genome-wide association; Psychosis; Schizophrenia; White matter; ZNF804A