title: The schizophrenia risk allele C of the TCF4 rs9960767 polymorphism disrupts sensorimotor gating in schizophrenia spectrum and healthy volunteers.
abstract: In a large-scale meta-analysis, it has been recently shown that the transcription factor 4 (TCF4) gene is among the most prominent susceptibility genes for schizophrenia. Moreover, transgenic mice overexpressing TCF4 in the brain display a reduction of sensorimotor gating measured by prepulse inhibition (PPI) of the acoustic startle response (ASR). PPI is heritable and has been established as an important translational endophenotype of schizophrenia. We therefore investigated the impact of the schizophrenia susceptibility gene TCF4 (rs9960767) on sensorimotor gating of the ASR in healthy humans and in patients with a schizophrenia spectrum disorder. We assessed PPI, startle reactivity, and habituation of the ASR in two independent samples. The first sample consisted of 107 healthy volunteers from London, UK. The second sample was a schizophrenia spectrum group (n = 113) of 73 schizophrenia patients and 40 individuals at high risk for schizophrenia from Bonn, Germany (total sample n = 220). In both samples, PPI was strongly decreased in carriers of the schizophrenia risk allele C of the TCF4 gene (meta-analysis across both samples: p = 0.00002), whereas startle reactivity and habituation were unaffected by TCF4 genotype. Sensorimotor gating is modulated by TCF4 genotype, indicating an influential role of TCF4 gene variations in the development of early information-processing deficits in schizophrenia.
authors.affiliation: University Hospital of Psychiatry, Division of Experimental and Clinical Pharmacopsychology, University of Zurich, CH-8032 Zurich, Switzerland. quednow@bli.uzh.ch
authors.forename: Boris B
authors.initials: BB
authors.lastname: Quednow
authors.forename: Ulrich
authors.initials: U
authors.lastname: Ettinger
authors.forename: Rainald
authors.initials: R
authors.lastname: Mössner
authors.forename: Dan
authors.initials: D
authors.lastname: Rujescu
authors.forename: Ina
authors.initials: I
authors.lastname: Giegling
authors.forename: David A
authors.initials: DA
authors.lastname: Collier
authors.forename: Anne
authors.initials: A
authors.lastname: Schmechtig
authors.forename: Kai-Uwe
authors.initials: KU
authors.lastname: Kühn
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Möller
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Maier
authors.forename: Michael
authors.initials: M
authors.lastname: Wagner
authors.forename: Veena
authors.initials: V
authors.lastname: Kumari
mesh_terms: D000161:Acoustic Stimulation; D000293:Adolescent; D000328:Adult; D000483:Alleles; D000704:Analysis of Variance; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D013216:Reflex, Startle / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics*; D055139:Sensory Gating / Q000235:genetics*; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors