title: Genetic variation in GAD1 is associated with cortical thickness in the parahippocampal gyrus.
abstract: Patients with schizophrenia show widespread cortical thickness reductions throughout the brain. Likewise, reduced expression of the γ-Aminobutyric acid (GABA) synthesizing enzyme glutamic acid decarboxylase (GAD1) and a single nucleotide polymorphism (SNP) rs3749034 in the corresponding gene have been associated with schizophrenia. We tested whether this SNP is associated with reduced cortical thickness, an intermediate phenotype for schizophrenia. Because of the well known interactions between the GABAergic and dopaminergic systems, we examined whether associations between GAD1 rs3749034 and cortical thickness are modulated by the catechol-O-methyltransferase (COMT) Val158Met genotype. Structural MRI and genotype data was obtained from 94 healthy subjects enrolled in the Mind Clinical Imaging Consortium study to examine the relations between GAD1 genotype and cortical thickness. Our data show a robust reduction of cortical thickness in the left parahippocampal gyrus (PHG) in G allele homozygotes of GAD1 rs3749034. When we stratified our analyses according to the COMT Val158Met genotype, cortical thickness reductions of G allele homozygotes were only found in the presence of the Val allele. Genetic risk variants of schizophrenia in the GABAergic system might interact with the dopaminergic system and impact brain structure and functioning. Our findings point to the importance of the GABAergic system in the pathogenesis of schizophrenia.
authors.affiliation: Department of Child and Adolescent Psychiatry, TU Dresden, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Brauns
authors.forename: Randy L
authors.initials: RL
authors.lastname: Gollub
authors.forename: Esther
authors.initials: E
authors.lastname: Walton
authors.forename: Johanna
authors.initials: J
authors.lastname: Hass
authors.forename: Michael N
authors.initials: MN
authors.lastname: Smolka
authors.forename: Tonya
authors.initials: T
authors.lastname: White
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Wassink
authors.forename: Vince D
authors.initials: VD
authors.lastname: Calhoun
authors.forename: Stefan
authors.initials: S
authors.lastname: Ehrlich
mesh_terms: D000293:Adolescent; D000328:Adult; D002394:Catechol O-Methyltransferase / Q000235:genetics; D016009:Chi-Square Distribution; D005260:Female; D005838:Genotype; D005968:Glutamate Decarboxylase / Q000235:genetics*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008715:Methionine / Q000235:genetics; D008875:Middle Aged; D020534:Parahippocampal Gyrus / Q000033:anatomy & histology* / Q000201:enzymology*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D014633:Valine / Q000235:genetics; D055815:Young Adult
chemical_list: D008715:Methionine; D002394:Catechol O-Methyltransferase; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; D014633:Valine