Systematic Integration of Brain eQTL and GWAS Identifies ZNF323 as a Novel Schizophrenia Risk Gene and Suggests Recent Positive Selection Based on Compensatory Advantage on Pulmonary Function
文献类型：期刊论文
| 作者 | Luo XJ[*]1; Mattheisen M2,3,4; Børglum AD2,3,8; Als TD2,3; van den Oord EJ9; Aberg KA9; Mors O3,10; Mortensen PB3,11; Li M5; Luo Z12 |
| 刊名 | SCHIZOPHRENIA BULLETIN
 |
| 出版日期 | 2015 |
| 卷号 | 41期号:6页码:1294-1308 |
| 关键词 | ZNF323 association eQTL hippocampus positive selection schizophrenia |
| 通讯作者 | luoxiongjian@mail.kiz.ac.cn |
| 合作状况 | 其它 |
| 英文摘要 | Genome-wide association studies have identified multiple risk variants and loci that show robust association with schizophrenia. Nevertheless, it remains unclear how these variants confer risk to schizophrenia. In addition, the driving force that maintains the schizophrenia risk variants in human gene pool is poorly understood. To investigate whether expression-associated genetic variants contribute to schizophrenia susceptibility, we systematically integrated brain expression quantitative trait loci and genome-wide association data of schizophrenia using Sherlock, a Bayesian statistical framework. Our analyses identified ZNF323 as a schizophrenia risk gene (P = 2.22×10-6). Subsequent analyses confirmed the association of the ZNF323 and its expression-associated single nucleotide polymorphism rs1150711 in independent samples (gene-expression: P = 1.40×10-6; single-marker meta-analysis in the combined discovery and replication sample comprising 44123 individuals: P = 6.85×10-10). We found that the ZNF323 was significantly downregulated in hippocampus and frontal cortex of schizophrenia patients (P = .0038 and P = .0233, respectively). Evidence for pleiotropic effects was detected (association of rs1150711 with lung function and gene expression of ZNF323 in lung: P = 6.62×10-5 and P = 9.00×10-5, respectively) with the risk allele (T allele) for schizophrenia acting as protective allele for lung function. Subsequent population genetics analyses suggest that the risk allele (T) of rs1150711 might have undergone recent positive selection in human population. Our findings suggest that the ZNF323 is a schizophrenia susceptibility gene whose expression may influence schizophrenia risk. Our study also illustrates a possible mechanism for maintaining schizophrenia risk variants in the human gene pool. |
| 收录类别 | SCI |
| 资助信息 | X.J.L was supported by the 100 Talents Program (BaiRenJiHua) of the Chinese Academy of Sciences. Y.G.Y was supported by the Strategic Priority Research Program (B) of the Chinese Academy of Sciences (XDB02020000). The research leading to these results has received funding from the European Community’s Seventh Framework Programme: FP7/ Health-2011-1.1-2 under grant agreement n°279227 and Health-F4-2009–242257 to M.R. (ADAMS proj- ect). This study was also supported by the German Federal Ministry of Education and Research (BMBF) through the Integrated Genome Research Network (IG) MooDS (Systematic Investigation of the Molecular Causes of Major Mood Disorders and Schizophrenia; grant 01GS08144 to M.M.N. and S.C., grant 01GS08147 to M.R.), under the auspices of the National Genome Research Network plus (NGFNplus), and through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders), under the auspices of the e:Med Programme. M.M.N. is a member of the DFG-funded Excellence-Cluster ImmunoSensation and also received support from the Alfried Krupp von Bohlen und Halbach-Stiftung. We thank the grant support from National Institutes of Health grant (R01LM011177). |
| 语种 | 英语 |
| 源URL | [http://159.226.149.26:8080/handle/152453/9337]  |
| 专题 | 昆明动物研究所_神经系统疾病 昆明动物研究所_动物模型与人类重大疾病机理重点实验室 昆明动物研究所_遗传资源与进化国家重点实验室 昆明动物研究所_比较基因组学 昆明动物研究所_重大疾病机理的遗传学 |
| 作者单位 | 1.Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China 2.Department of Biomedicine and Centre for Integrative Sequencing (iSEQ), Aarhus University, 8000 Aarhus C, Denmark 3.The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus and Copenhagen, Denmark 4.Department of Genomics, Life & Brain Center, and Institute of Human Genetics, University of Bonn, Bonn, Germany 5.Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 6.First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China 7.Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany 8.Research Department, Psychiatric Hospital, Aarhus University Hospital, Aarhus, Denmark 9.Center for Biomarker Research and Personalized Medicine, Virginia Commonwealth University 10.Centre for Psychiatric Research, Aarhus University Hospital, Risskov, Denmark |
| 推荐引用方式 GB/T 7714 | Luo XJ[*],Mattheisen M,Børglum AD,et al. Systematic Integration of Brain eQTL and GWAS Identifies ZNF323 as a Novel Schizophrenia Risk Gene and Suggests Recent Positive Selection Based on Compensatory Advantage on Pulmonary Function[J]. SCHIZOPHRENIA BULLETIN,2015,41(6):1294-1308. |
| APA | Luo XJ[*].,Mattheisen M.,Børglum AD.,Als TD.,van den Oord EJ.,...&Rietschel M.(2015).Systematic Integration of Brain eQTL and GWAS Identifies ZNF323 as a Novel Schizophrenia Risk Gene and Suggests Recent Positive Selection Based on Compensatory Advantage on Pulmonary Function.SCHIZOPHRENIA BULLETIN,41(6),1294-1308. |
| MLA | Luo XJ[*],et al."Systematic Integration of Brain eQTL and GWAS Identifies ZNF323 as a Novel Schizophrenia Risk Gene and Suggests Recent Positive Selection Based on Compensatory Advantage on Pulmonary Function".SCHIZOPHRENIA BULLETIN 41.6(2015):1294-1308. |
入库方式： OAI收割
来源：昆明动物研究所
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