title: Genetic association of ErbB4 and human cortical GABA levels in vivo.
abstract: NRG1-ErbB4 signaling controls inhibitory circuit development in the mammalian cortex through ErbB4-dependent regulation of GABAergic interneuron connectivity. Common genetic variation in ErbB4 (rs7598440) has been associated with ErbB4 messenger RNA levels in the human cortex and risk for schizophrenia. Recent work demonstrates that Erbb4 is expressed exclusively on inhibitory interneurons, where its presence on parvalbumin-positive cells mediates the effects of NRG1 on inhibitory circuit formation in the cortex. We therefore hypothesized that genetic variation in ErbB4 at rs7598440 would impact indices of GABA concentration in the human cortex. We tested this hypothesis in 116 healthy volunteers by measuring GABA and GLX (glutamate + glutamine) with proton magnetic resonance spectroscopy in the dorsal anterior cingulate gyrus. ErbB4 rs7598440 genotype significantly predicted cortical GABA concentration (p = 0.014), but not GLX (p = 0.51), with A allele carriers having higher GABA as predicted by the allelic impact on ErbB4 expression. These data establish an association of ErbB4 and GABA in human brain and have implications for understanding the pathogenesis of schizophrenia and other psychiatric disorders.
authors.affiliation: Unit for Multimodal Imaging Genetics, Clinical Brain Disorders Branch, Genes Cognition and Psychosis Program, NIH, Bethesda, Maryland 20892, USA. marencos@mail.nih.gov
authors.forename: Stefano
authors.initials: S
authors.lastname: Marenco
authors.forename: Matthew
authors.initials: M
authors.lastname: Geramita
authors.forename: Jan Willem
authors.initials: JW
authors.lastname: van der Veen
authors.forename: Alan S
authors.initials: AS
authors.lastname: Barnett
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Kolachana
authors.forename: Jun
authors.initials: J
authors.lastname: Shen
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Weinberger
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Law
mesh_terms: D000241:Adenosine / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000483:Alleles; D002540:Cerebral Cortex / Q000737:chemistry / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D066247:Receptor, ErbB-4; D055815:Young Adult; D005680:gamma-Aminobutyric Acid / Q000235:genetics* / Q000378:metabolism*
chemical_list: D005680:gamma-Aminobutyric Acid; C587689:ERBB4 protein, human; D066246:ErbB Receptors; D066247:Receptor, ErbB-4; D000241:Adenosine