title: Association of Common Polymorphisms in the Nicotinic Acetylcholine Receptor Alpha4 Subunit Gene with an Electrophysiological Endophenotype in a Large Population-Based Sample.
abstract: Variation in genes coding for nicotinic acetylcholine receptor (nAChR) subunits affect cognitive processes and may contribute to the genetic architecture of neuropsychiatric disorders. Single nucleotide polymorphisms (SNPs) in the CHRNA4 gene that codes for the alpha4 subunit of alpha4/beta2-containing receptors have previously been implicated in aspects of (mostly visual) attention and smoking-related behavioral measures. Here we investigated the effects of six synonymous but functional CHRNA4 exon 5 SNPs on the N100 event-related potential (ERP), an electrophysiological endophenotype elicited by a standard auditory oddball. A total of N = 1,705 subjects randomly selected from the general population were studied with electroencephalography (EEG) as part of the German Multicenter Study on nicotine addiction. Two of the six variants, rs1044396 and neighboring rs1044397, were significantly associated with N100 amplitude. This effect was pronounced in females where we also observed an effect on reaction time. Sequencing of the complete exon 5 region in the population sample excluded the existence of additional/functional variants that may be responsible for the observed effects. This is the first large-scale population-based study investigation the effects of CHRNA4 SNPs on brain activity measures related to stimulus processing and attention. Our results provide further evidence that common synonymous CHRNA4 exon 5 SNPs affect cognitive processes and suggest that they also play a role in the auditory system. As N100 amplitude reduction is considered a schizophrenia-related endophenotype the SNPs studied here may also be associated with schizophrenia outcome measures.
authors.affiliation: Department of Psychiatry, Mainz University Hospital, Mainz, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Mobascher
authors.affiliation: Cologne Center for Genomics, University of Cologne, Cologne, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Diaz-Lacava
authors.affiliation: Department of Psychiatry, Bonn University Hospital, Bonn, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Wagner
authors.affiliation: Department of Psychiatry and Psychotherapy, University Medical Center Hamburg Eppendorf (UKE), Hamburg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Gallinat
authors.affiliation: Max-Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: T F
authors.initials: TF
authors.lastname: Wienker
authors.affiliation: University of Greifswald, Greifswald, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Drichel
authors.affiliation: University of Greifswald, Greifswald, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Becker
authors.affiliation: Research Division, Federal Institute for Drugs and Medical Devices (BfArM), Bonn, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Steffens
authors.affiliation: Department of Psychiatry, Mainz University Hospital, Mainz, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Dahmen
authors.affiliation: Department of Psychiatry, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen, University Hospital, Aachen, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Gründer
authors.affiliation: Department of Psychiatry, Friedrich-Alexander University, University Hospital, Erlangen- Nürnberg, Erlangen, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Thürauf
authors.affiliation: Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Mannheim, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Kiefer
authors.affiliation: Department of Psychiatry, Friedrich-Alexander University, University Hospital, Erlangen- Nürnberg, Erlangen, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Kornhuber
authors.affiliation: Cologne Center for Genomics, University of Cologne, Cologne, Germany.
authors.forename: M R
authors.initials: MR
authors.lastname: Toliat
authors.affiliation: Cologne Center for Genomics, University of Cologne, Cologne, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Thiele
authors.affiliation: Cologne Center for Genomics, University of Cologne, Cologne, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: Department of Human Genetics, Ludwig-Maximilians University, Munich, Germany.
authors.forename: O
authors.initials: O
authors.lastname: Steinlein
authors.affiliation: Experimental and Clinical Research Center (ECRC), Charité - University Medicine, Berlin, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Winterer
mesh_terms: D000328:Adult; D055724:Electrophysiological Phenomena; D058068:Endophenotypes; D005260:Female; D005858:Germany / Q000453:epidemiology; D006801:Humans; D008297:Male; D059906:Neuroimaging; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011978:Receptors, Nicotinic / Q000235:genetics*; D012907:Smoking / Q000009:adverse effects*; D014029:Tobacco Use Disorder / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology
chemical_list: D011978:Receptors, Nicotinic