title: Schizophrenia risk polymorphisms in the TCF4 gene interact with smoking in the modulation of auditory sensory gating.
abstract: Several polymorphisms of the transcription factor 4 (TCF4) have been shown to increase the risk for schizophrenia, particularly TCF4 rs9960767. This polymorphism is associated with impaired sensorimotor gating measured by prepulse inhibition--an established endophenotype of schizophrenia. We therefore investigated whether TCF4 polymorphisms also affect another proposed endophenotype of schizophrenia, namely sensory gating assessed by P50 suppression of the auditory evoked potential. Although sensorimotor gating and sensory gating are not identical, recent data suggest that they share genetic fundamentals. In a multicenter study at six academic institutions throughout Germany, we applied an auditory P50 suppression paradigm to 1,821 subjects (1,023 never-smokers, 798 smokers) randomly selected from the general population. Samples were genotyped for 21 TCF4 polymorphisms. Given that smoking is highly prevalent in schizophrenia and affects sensory gating, we also assessed smoking behavior, cotinine plasma concentrations, exhaled carbon monoxide, and the Fagerström Test (FTND). P50 suppression was significantly decreased in carriers of schizophrenia risk alleles of the TCF4 polymorphisms rs9960767, rs10401120rs, rs17597926, and 17512836 (P < 0.0002-0.00005). These gene effects were modulated by smoking behavior as indicated by significant interactions of TCF4 genotype and smoking status; heavy smokers (FTND score ≥ 4) showed stronger gene effects on P50 suppression than light smokers and never-smokers. Our finding suggests that sensory gating is modulated by an interaction of TCF4 genotype with smoking, and both factors may play a role in early information processing deficits also in schizophrenia. Consequently, considering smoking behavior may facilitate the search for genetic risk factors for schizophrenia.
authors.affiliation: Experimental and Clinical Pharmacopsychology, Clinic for Affective Disorders and General Psychiatry,  University Hospital of Psychiatry Zurich, 8032 Zurich,  Switzerland.
authors.forename: Boris B
authors.initials: BB
authors.lastname: Quednow
authors.forename: Jürgen
authors.initials: J
authors.lastname: Brinkmeyer
authors.forename: Arian
authors.initials: A
authors.lastname: Mobascher
authors.forename: Michael
authors.initials: M
authors.lastname: Nothnagel
authors.forename: Francesco
authors.initials: F
authors.lastname: Musso
authors.forename: Gerhard
authors.initials: G
authors.lastname: Gründer
authors.forename: Noah
authors.initials: N
authors.lastname: Savary
authors.forename: Nadine
authors.initials: N
authors.lastname: Petrovsky
authors.forename: Ingo
authors.initials: I
authors.lastname: Frommann
authors.forename: Leonhard
authors.initials: L
authors.lastname: Lennertz
authors.forename: Katja N
authors.initials: KN
authors.lastname: Spreckelmeyer
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Wienker
authors.forename: Norbert
authors.initials: N
authors.lastname: Dahmen
authors.forename: Norbert
authors.initials: N
authors.lastname: Thuerauf
authors.forename: Marion
authors.initials: M
authors.lastname: Clepce
authors.forename: Falk
authors.initials: F
authors.lastname: Kiefer
authors.forename: Tomislav
authors.initials: T
authors.lastname: Majic
authors.forename: Rainald
authors.initials: R
authors.lastname: Mössner
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Maier
authors.forename: Jürgen
authors.initials: J
authors.lastname: Gallinat
authors.forename: Amalia
authors.initials: A
authors.lastname: Diaz-Lacava
authors.forename: Mohammad R
authors.initials: MR
authors.lastname: Toliat
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Michael
authors.initials: M
authors.lastname: Wagner
authors.forename: Georg
authors.initials: G
authors.lastname: Winterer
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics*; D003367:Cotinine / Q000097:blood; D004569:Electroencephalography; D005072:Evoked Potentials, Auditory / Q000502:physiology; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D005843:Geography; D005858:Germany; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012559:Schizophrenia / Q000235:genetics* / Q000503:physiopathology*; D055139:Sensory Gating / Q000502:physiology*; D012907:Smoking / Q000097:blood / Q000503:physiopathology*; 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; D003367:Cotinine