title: 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.
abstract: 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.
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China; These authors contributed equally to this work. luoxiongjian@mail.kiz.ac.cn.
authors.forename: Xiong-Jian
authors.initials: XJ
authors.lastname: Luo
authors.affiliation: Department of Biomedicine and Centre for Integrative Sequencing (iSEQ), Aarhus University, 8000 Aarhus C, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus and Copenhagen, Denmark; Department of Genomics, Life & Brain Center, and Institute of Human Genetics, University of Bonn, Bonn, Germany; These authors contributed equally to this work.
authors.forename: Manuel
authors.initials: M
authors.lastname: Mattheisen
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD;
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.affiliation: First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China;
authors.forename: Liang
authors.initials: L
authors.lastname: Huang
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany;
authors.forename: Marcella
authors.initials: M
authors.lastname: Rietschel
authors.affiliation: Department of Biomedicine and Centre for Integrative Sequencing (iSEQ), Aarhus University, 8000 Aarhus C, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus and Copenhagen, Denmark; Research Department, Psychiatric Hospital, Aarhus University Hospital, Aarhus, Denmark;
authors.forename: Anders D
authors.initials: AD
authors.lastname: Børglum
authors.affiliation: Department of Biomedicine and Centre for Integrative Sequencing (iSEQ), Aarhus University, 8000 Aarhus C, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus and Copenhagen, Denmark;
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Als
authors.affiliation: Center for Biomarker Research and Personalized Medicine, Virginia Commonwealth University;
authors.forename: Edwin J
authors.initials: EJ
authors.lastname: van den Oord
authors.affiliation: Center for Biomarker Research and Personalized Medicine, Virginia Commonwealth University;
authors.forename: Karolina A
authors.initials: KA
authors.lastname: Aberg
authors.affiliation: The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus and Copenhagen, Denmark; Centre for Psychiatric Research, Aarhus University Hospital, Risskov, Denmark;
authors.forename: Ole
authors.initials: O
authors.lastname: Mors
authors.affiliation: The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus and Copenhagen, Denmark; National Centre for Register-based Research, Aarhus University, Aarhus, Denmark;
authors.forename: Preben Bo
authors.initials: PB
authors.lastname: Mortensen
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC;
authors.forename: Zhenwu
authors.initials: Z
authors.lastname: Luo
authors.affiliation: Department of Genomics, Life & Brain Center, and Institute of Human Genetics, University of Bonn, Bonn, Germany;
authors.forename: Franziska
authors.initials: F
authors.lastname: Degenhardt
authors.affiliation: Division of Medical Genetics, Department of Biomedicine, University Basel, Basel, Switzerland; Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Juelich, Germany;
authors.forename: Sven
authors.initials: S
authors.lastname: Cichon
authors.affiliation: Department of Psychiatry and Psychotherapy, University Medical Center Georg-August-Universität, 37075 Goettingen, Germany; Institute of Psychiatric Phenomics and Genomics (IPPG), Ludwig-Maximilians-University Munich;
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Schulze
authors.affiliation: Department of Genomics, Life & Brain Center, and Institute of Human Genetics, University of Bonn, Bonn, Germany;
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.affiliation: State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China;
authors.forename: Bing
authors.initials: B
authors.lastname: Su
authors.affiliation: Departments of Biomedical Informatics and Psychiatry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA;
authors.forename: Zhongming
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Departments of Biomedical Informatics and Psychiatry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA;
authors.forename: Lin
authors.initials: L
authors.lastname: Gan
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China; CAS Center for Excellence in Brain Science, Chinese Academy of Sciences, Shanghai, 200031, China.
authors.forename: Yong-Gang
authors.initials: YG
authors.lastname: Yao
mesh_terms: D004268:DNA-Binding Proteins / Q000235:genetics*; D015536:Down-Regulation; D005625:Frontal Lobe / Q000378:metabolism*; D015870:Gene Expression / Q000235:genetics*; D058685:Genetic Pleiotropy / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000235:genetics*; D012306:Risk; D012559:Schizophrenia / Q000235:genetics*; D012641:Selection, Genetic / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D014157:Transcription Factors; C464855:ZSCAN31 protein, human
keywords: ZNF323; association; eQTL; hippocampus; positive selection; schizophrenia