title: Evaluating the dopamine hypothesis of schizophrenia in a large-scale genome-wide association study.
abstract: The dopamine hypothesis, which posits that dysregulation of the dopaminergic system is etiologic for schizophrenia, is among the most enduring biological theories in psychiatry. Although variation within genes related to dopaminergic functioning has been associated with schizophrenia, an aggregate test of variation, using the largest publicly available schizophrenia dataset, has not previously been conducted.
  
  
  
  We first identified a core set of 11 genes involved in the synthesis, metabolism, and neurotransmission of dopamine. We then extracted summary statistics of markers falling within, or flanking, these genes from the Psychiatric Genomics Consortium's most recent schizophrenia mega-analysis results. We conducted aggregate tests for enrichment of dopamine-related pathways for association with schizophrenia.
  
  
  
  We did not detect significant enrichment of signals across the core set of dopamine-related genes. However, we did observe modest to strong enrichment of genetic signals within the DRD2 locus.
  
  
  
  Within the limits of available power, common sequence variation within core genes of the dopaminergic system is not related to risk of schizophrenia. This does not preclude a role of dopamine, or dopamine-related genes, in the clinical presentation of schizophrenia or in treatment response. However, it does suggest that the genetic risk for schizophrenia is not substantially affected by common variation in those genes which, collectively, critically impact dopaminergic functioning.
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, PO Box 980126, Richmond, VA 23298-0126, United States. Electronic address: alexis.edwards@vcuhealth.org.
authors.forename: Alexis C
authors.initials: AC
authors.lastname: Edwards
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, PO Box 980126, Richmond, VA 23298-0126, United States.
authors.forename: Silviu-Alin
authors.initials: SA
authors.lastname: Bacanu
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, PO Box 980126, Richmond, VA 23298-0126, United States.
authors.forename: Tim B
authors.initials: TB
authors.lastname: Bigdeli
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, PO Box 980126, Richmond, VA 23298-0126, United States.
authors.forename: Arden
authors.initials: A
authors.lastname: Moscati
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, PO Box 980126, Richmond, VA 23298-0126, United States.
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Kendler
mesh_terms: D004298:Dopamine / Q000378:metabolism*; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium; D016571:Neural Networks, Computer; D017448:Receptors, Dopamine D2 / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism*
chemical_list: C581293:DRD2 protein, human; D017448:Receptors, Dopamine D2; D004298:Dopamine
keywords: Dopamine hypothesis of schizophrenia; Genetic risk; Statistical enrichment