Genome-wide discovered psychosis-risk gene ZNF804A impacts on white matter microstructure in health, schizophrenia and bipolar disorder
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 corre...
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2016-02-01
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| author | Emma-Jane Mallas Francesco Carletti Christopher A. Chaddock James Woolley Marco M. Picchioni Sukhwinder S. Shergill Fergus Kane Matthew P.G. Allin Gareth J. Barker Diana P. Prata |
| author_facet | Emma-Jane Mallas Francesco Carletti Christopher A. Chaddock James Woolley Marco M. Picchioni Sukhwinder S. Shergill Fergus Kane Matthew P.G. Allin Gareth J. Barker Diana P. Prata |
| author_sort | Emma-Jane Mallas |
| collection | DOAJ |
| container_title | PeerJ |
| description | 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. |
| format | Article |
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| institution | Directory of Open Access Journals |
| issn | 2167-8359 |
| language | English |
| publishDate | 2016-02-01 |
| publisher | PeerJ Inc. |
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| spelling | doaj-art-80faab465d8a4e6aafc832f8a5a2bee22025-08-20T00:33:24ZengPeerJ Inc.PeerJ2167-83592016-02-014e157010.7717/peerj.1570Genome-wide discovered psychosis-risk gene ZNF804A impacts on white matter microstructure in health, schizophrenia and bipolar disorderEmma-Jane Mallas0Francesco Carletti1Christopher A. Chaddock2James Woolley3Marco M. Picchioni4Sukhwinder S. Shergill5Fergus Kane6Matthew P.G. Allin7Gareth J. Barker8Diana P. Prata9Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, University of London, London, United KingdomDepartment of Neuroradiology, John Radcliffe Hospital, Oxford University Hospitals NHS Trust, Oxford, United KingdomDepartment of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, University of London, London, United KingdomPsychological Medicine, Royal Brompton & Harefield NHS Trust, London, United KingdomDepartment of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, University of London, London, United KingdomDepartment of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, University of London, London, United KingdomDepartment of Psychology, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, University of London, London, United KingdomDepartment of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, University of London, London, United KingdomDepartment of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, University of London, London, United KingdomDepartment of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, University of London, London, United KingdomBackground. 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.https://peerj.com/articles/1570.pdfGenome-wide associationWhite matterZNF804APsychosisFractional anisotropyDiffusion tensor imaging |
| spellingShingle | Emma-Jane Mallas Francesco Carletti Christopher A. Chaddock James Woolley Marco M. Picchioni Sukhwinder S. Shergill Fergus Kane Matthew P.G. Allin Gareth J. Barker Diana P. Prata Genome-wide discovered psychosis-risk gene ZNF804A impacts on white matter microstructure in health, schizophrenia and bipolar disorder Genome-wide association White matter ZNF804A Psychosis Fractional anisotropy Diffusion tensor imaging |
| title | Genome-wide discovered psychosis-risk gene ZNF804A impacts on white matter microstructure in health, schizophrenia and bipolar disorder |
| title_full | Genome-wide discovered psychosis-risk gene ZNF804A impacts on white matter microstructure in health, schizophrenia and bipolar disorder |
| title_fullStr | Genome-wide discovered psychosis-risk gene ZNF804A impacts on white matter microstructure in health, schizophrenia and bipolar disorder |
| title_full_unstemmed | Genome-wide discovered psychosis-risk gene ZNF804A impacts on white matter microstructure in health, schizophrenia and bipolar disorder |
| title_short | Genome-wide discovered psychosis-risk gene ZNF804A impacts on white matter microstructure in health, schizophrenia and bipolar disorder |
| title_sort | genome wide discovered psychosis risk gene znf804a impacts on white matter microstructure in health schizophrenia and bipolar disorder |
| topic | Genome-wide association White matter ZNF804A Psychosis Fractional anisotropy Diffusion tensor imaging |
| url | https://peerj.com/articles/1570.pdf |
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