title: Integrating GWASs and human protein interaction networks identifies a gene subnetwork underlying alcohol dependence.
abstract: Despite a significant genetic contribution to alcohol dependence (AD), few AD-risk genes have been identified to date. In the current study, we aimed to integrate genome-wide association studies (GWASs) and human protein interaction networks to investigate whether a subnetwork of genes whose protein products interact with one another might collectively contribute to AD. By using two discovery GWAS data sets of the Study of Addiction: Genetics and Environment (SAGE) and the Collaborative Study on the Genetics of Alcoholism (COGA), we identified a subnetwork of 39 genes that not only was enriched for genes associated with AD, but also collectively associated with AD in both European Americans (p < 0.0001) and African Americans (p = 0.0008). We replicated the association of the gene subnetwork with AD in three independent samples, including two samples of European descent (p = 0.001 and p = 0.006) and one sample of African descent (p = 0.0069). To evaluate whether the significant associations are likely to be false-positive findings and to ascertain their specificity, we examined the same gene subnetwork in three other human complex disorders (bipolar disorder, major depressive disorder, and type 2 diabetes) and found no significant associations. Functional enrichment analysis revealed that the gene subnetwork was enriched for genes involved in cation transport, synaptic transmission, and transmission of nerve impulses, all of which are biologically meaningful processes that may underlie the risk for AD. In conclusion, we identified a gene subnetwork underlying AD that is biologically meaningful and highly reproducible, providing important clues for future research into AD etiology and treatment.
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06510, USA; Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA 55242, USA. Electronic address: shizhong-han@uiowa.edu.
authors.forename: Shizhong
authors.initials: S
authors.lastname: Han
authors.forename: Bao-Zhu
authors.initials: BZ
authors.lastname: Yang
authors.forename: Henry R
authors.initials: HR
authors.lastname: Kranzler
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Liu
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhao
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Farrer
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.forename: James B
authors.initials: JB
authors.lastname: Potash
authors.forename: Joel
authors.initials: J
authors.lastname: Gelernter
mesh_terms: D000437:Alcoholism / Q000235:genetics* / Q000378:metabolism*; D016022:Case-Control Studies; D019295:Computational Biology; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D006801:Humans; D020412:Multifactorial Inheritance / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D060066:Protein Interaction Maps