22
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      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

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          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.

          Related collections

          Author and article information

          Journal
          Schizophr Bull
          Schizophr Bull
          schbul
          schbul
          Schizophrenia Bulletin
          Oxford University Press (US )
          0586-7614
          1745-1701
          November 2015
          10 March 2015
          : 41
          : 6
          : 1294-1308
          Affiliations
          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;
          11 National Centre for Register-based Research, Aarhus University , Aarhus, Denmark;
          12 Department of Microbiology and Immunology, Medical University of South Carolina , Charleston, SC;
          13 Division of Medical Genetics, Department of Biomedicine, University Basel , Basel, Switzerland;
          14 Institute of Neuroscience and Medicine (INM-1), Research Center Juelich , Juelich, Germany;
          15 Department of Psychiatry and Psychotherapy, University Medical Center Georg-August-Universität , 37075 Goettingen, Germany;
          16 Institute of Psychiatric Phenomics and Genomics (IPPG) , Ludwig-Maximilians-University Munich;
          17 State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences , Kunming, Yunnan, China;
          18 Departments of Biomedical Informatics and Psychiatry, Vanderbilt University School of Medicine , Nashville, TN 37232, USA;
          19 Flaum Eye Institute and Department of Ophthalmology, University of Rochester , Rochester, NY 14642, USA;
          20 CAS Center for Excellence in Brain Science, Chinese Academy of Sciences , Shanghai, 200031, China
          21These authors contributed equally to this work.
          A full list of the members is provided in the supplementary data online.
          A full list of the members is provided in the supplementary data online.
          Author notes
          *To whom correspondence should be addressed; Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China; tel: 86-18787077938, fax: 86-871-65180085, e-mail: luoxiongjian@ 123456mail.kiz.ac.cn
          Article
          PMC4601704 PMC4601704 4601704
          10.1093/schbul/sbv017
          4601704
          25759474
          ea608031-e9de-4c65-b034-2f18aca1e30b
          © The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com
          History
          Page count
          Pages: 15
          Categories
          Regular Article

          schizophrenia, ZNF323 ,association,eQTL,hippocampus,positive selection

          Comments

          Comment on this article