Genome-wide discovered psychosis-risk gene ZNF804A impacts on white matter microstructure in health, schizophrenia and bipolar disorder

Author:

Mallas Emma-Jane12,Carletti Francesco3,Chaddock Christopher A.1,Woolley James4,Picchioni Marco M.15,Shergill Sukhwinder S.1,Kane Fergus6,Allin Matthew P.G.1,Barker Gareth J.7,Prata Diana P.78

Affiliation:

1. Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, University of London, London, United Kingdom

2. Computational, Cognitive and Clinical Neuroimaging Laboratory, Division of Brain Sciences, Department of Medicine, Imperial College London, London, United Kingdom

3. Department of Neuroradiology, John Radcliffe Hospital, Oxford University Hospitals NHS Trust, Oxford, United Kingdom

4. Psychological Medicine, Royal Brompton & Harefield NHS Trust, London, United Kingdom

5. St Andrew’s Academic Department, St Andrew’s Healthcare, Northampton, United Kingdom

6. Department of Psychology, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, University of London, London, United Kingdom

7. Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, University of London, London, United Kingdom

8. Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal

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 betweenZNF804Ars1344706 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.

Funder

UK National Institute for Health Research fellowship

Fundação para a Ciência e Tecnologia Investigator

Publisher

PeerJ

Subject

General Agricultural and Biological Sciences,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

Reference95 articles.

1. White matter and cognition in adults who were born preterm;Allin;PLoS ONE,2011

2. DSM-IV. APATFo;American Psychiatric Association,1994

3. Permutation tests for linear models;Anderson;Australian & New Zealand Journal of Statistics,2001

4. Non-linear registration, aka Spatial normalisation,2007

5. Non-linear optimisation,2007

Cited by 25 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3