title: Analysis of Rare Variants in the Alcohol Dependence Candidate Gene GATA4.
abstract: Common variants in the gene GATA binding protein 4 (GATA4) show association with alcohol dependence (AD). The aim of this study was to identify rare variants in GATA4 in order to elucidate the role of this gene in AD susceptibility. Identification of rare variants may provide a more complete picture of the allelic architecture at this risk locus.
  
  
  
  Sanger sequencing of all 6 coding exons of GATA4 was performed in 528 patients and 517 controls. Four in silico prediction tools were used to determine the effect of a DNA variant on the amino acid sequence and protein function. Five variants were included in the replication step. Of these, 4 were successfully genotyped in our replication cohort of 655 patients and 1,501 controls. All patients fulfilled DSM-IV criteria for AD, and all individuals were of German descent.
  
  
  
  In the discovery step, 19 different heterozygous variants were identified. Four patient-specific and potentially functionally relevant variants were followed up. Only the variant S379S (c.1137C>T) remained patient specific (1/1,166 patients vs. 0/1,997 controls). None of the variants showed a statistically significant association with AD.
  
  
  
  The present study elucidated the role of GATA4 in AD susceptibility by identifying rare variants via Sanger sequencing and subsequent replication. Although novel patient-specific rare variants of GATA4 were identified, none received support in the independent replication step. However, given previous robust findings of association with common variants, GATA4 remains a promising candidate gene for AD.
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Degenhardt
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Laurenz
authors.initials: L
authors.lastname: Krämer
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Josef
authors.initials: J
authors.lastname: Frank
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Treutlein
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Heilmann-Heimbach
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.|Institute of Genomic Mathematics, University of Bonn, Bonn, Germany.
authors.forename: Julian
authors.initials: J
authors.lastname: Hecker
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.|Institute of Genomic Mathematics, University of Bonn, Bonn, Germany.|Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts.
authors.forename: Heide Löhlein
authors.initials: HL
authors.lastname: Fier
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Maren
authors.initials: M
authors.lastname: Lang
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Stephanie H
authors.initials: SH
authors.lastname: Witt
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Koller
authors.affiliation: Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Heidelberg University, Mannheim, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Mann
authors.affiliation: Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Heidelberg University, Mannheim, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Hoffmann
authors.affiliation: Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Heidelberg University, Mannheim, Germany.
authors.forename: Falk
authors.initials: F
authors.lastname: Kiefer
authors.affiliation: Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Spanagel
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Marcella
authors.initials: M
authors.lastname: Rietschel
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
mesh_terms: D000328:Adult; D000437:Alcoholism / Q000175:diagnosis* / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D050991:GATA4 Transcription Factor / Q000235:genetics*; D056726:Genetic Association Studies / Q000379:methods*; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged
chemical_list: D050991:GATA4 Transcription Factor; C484170:GATA4 protein, human
keywords: Alcohol Dependence; Common Variants; GATA4; Genetic Risk Factor; Rare Variants