title: Association of SNPs in EGR3 and ARC with Schizophrenia Supports a Biological Pathway for Schizophrenia Risk.
abstract: We have previously hypothesized a biological pathway of activity-dependent synaptic plasticity proteins that addresses the dual genetic and environmental contributions to schizophrenia. Accordingly, variations in the immediate early gene EGR3, and its target ARC, should influence schizophrenia susceptibility. We used a pooled Next-Generation Sequencing approach to identify variants across these genes in U.S. populations of European (EU) and African (AA) descent. Three EGR3 and one ARC SNP were selected and genotyped for validation, and three SNPs were tested for association in a replication cohort. In the EU group of 386 schizophrenia cases and 150 controls EGR3 SNP rs1877670 and ARC SNP rs35900184 showed significant associations (p = 0.0078 and p = 0.0275, respectively). In the AA group of 185 cases and 50 controls, only the ARC SNP revealed significant association (p = 0.0448). The ARC SNP did not show association in the Han Chinese (CH) population. However, combining the EU, AA, and CH groups revealed a highly significant association of ARC SNP rs35900184 (p = 2.353 x 10(-7); OR [95% CI] = 1.54 [1.310-1.820]). These findings support previously reported associations between EGR3 and schizophrenia. Moreover, this is the first report associating an ARC SNP with schizophrenia and supports recent large-scale GWAS findings implicating the ARC complex in schizophrenia risk. These results support the need for further investigation of the proposed pathway of environmentally responsive, synaptic plasticity-related, schizophrenia genes.
authors.affiliation: Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Huentelman
authors.affiliation: Department of Basic Medical Sciences, University of Arizona College of Medicine-Phoenix, Phoenix, Arizona, United States of America.
authors.forename: Leela
authors.initials: L
authors.lastname: Muppana
authors.affiliation: Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Corneveaux
authors.affiliation: Department of Biomedical Informatics, Arizona State University, Scottsdale, Arizona, United States of America.
authors.forename: Valentin
authors.initials: V
authors.lastname: Dinu
authors.affiliation: Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Pruzin
authors.affiliation: Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Reiman
authors.affiliation: Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
authors.forename: Cassie N
authors.initials: CN
authors.lastname: Borish
authors.affiliation: Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
authors.forename: Matt
authors.initials: M
authors.lastname: De Both
authors.affiliation: Department of Basic Medical Sciences, University of Arizona College of Medicine-Phoenix, Phoenix, Arizona, United States of America.
authors.forename: Amber
authors.initials: A
authors.lastname: Ahmed
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Todorov
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: C Robert
authors.initials: CR
authors.lastname: Cloninger
authors.affiliation: Xi'an Hong Hui Hospital, the Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Basic Medical Sciences, University of Arizona College of Medicine-Phoenix, Phoenix, Arizona, United States of America.
authors.forename: Amelia L
authors.initials: AL
authors.lastname: Gallitano
mesh_terms: D044466:Asian People; D002681:China / Q000208:ethnology; D003598:Cytoskeletal Proteins / Q000235:genetics*; D051776:Early Growth Response Protein 3 / Q000235:genetics*; D005260:Female; D060005:Genotyping Techniques; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012559:Schizophrenia / Q000208:ethnology / Q000235:genetics*
chemical_list: D003598:Cytoskeletal Proteins; C079945:EGR3 protein, human; D009419:Nerve Tissue Proteins; C092069:activity regulated cytoskeletal-associated protein; D051776:Early Growth Response Protein 3