title: Gene-based and pathway-based genome-wide association study of alcohol dependence.
abstract: BACKGROUND
  The organization of risk genes within signaling pathways may provide clues about the converging neurobiological effects of risk genes for alcohol dependence.
  
  
  OBJECTIVE
  Identify risk genes and risk gene pathways for alcohol dependence.
  
  
  METHODS
  We conducted a pathway-based genome-wide association study (GWAS) of alcohol dependence using a gene-set-rich analytic approach. Approximately one million genetic markers were tested in the discovery sample which included 1409 European-American (EA) alcohol dependent individuals and 1518 EA healthy comparison subjects. An additional 681 African-American (AA) cases and 508 AA healthy subjects served as the replication sample.
  
  
  RESULTS
  We identified several genome-wide replicable risk genes and risk pathways that were significantly associated with alcohol dependence. After applying the Bonferroni correction for multiple testing, the 'cellextracellular matrix interactions' pathway (p<2.0E-4 in EAs) and the PXN gene (which encodes paxillin) (p=3.9E-7 in EAs) within this pathway were the most promising risk factors for alcohol dependence. There were also two nominally replicable pathways enriched in alcohol dependence-related genes in both EAs (0.015≤p≤0.035) and AAs (0.025≤p≤0.050): the 'Na+/Cl- dependent neurotransmitter transporters' pathway and the 'other glycan degradation' pathway.
  
  
  CONCLUSIONS
  These findings provide new evidence highlighting several genes and biological signaling processes that may be related to the risk for alcohol dependence.
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States.
authors.forename: Lingjun
authors.initials: L
authors.lastname: Zuo
authors.affiliation: Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, CT, United States ; Biostatistics Resource, Keck Laboratory, Department of Genetics, Yale University School of Medicine, New Haven, CT, United States.
authors.forename: Clarence K
authors.initials: CK
authors.lastname: Zhang
authors.affiliation: Center for Medical Informatics, Yale University School of Medicine, New Haven, CT, United States ; Cooperative Studies Program Coordinating Center, VA Connecticut Healthcare System, West Haven, CT, United States.
authors.forename: Frederick G
authors.initials: FG
authors.lastname: Sayward
authors.affiliation: Center for Medical Informatics, Yale University School of Medicine, New Haven, CT, United States.
authors.forename: Kei-Hoi
authors.initials: KH
authors.lastname: Cheung
authors.affiliation: Department of Biostatistics and Epidemiology, College of Public Health, East Tennessee State University, Johnson City, TN, United States.
authors.forename: Kesheng
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States.
authors.forename: John H
authors.initials: JH
authors.lastname: Krystal
authors.affiliation: Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, CT, United States.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States.
authors.forename: Xingguang
authors.initials: X
authors.lastname: Luo
keywords: PXN; alcohol dependence; cell-extracellular matrix interaction pathway; gene-based GWAS; pathway-based GWAS; paxillin