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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.

journal_name

Am J Hum Genet

journal_title

American journal of human genetics

authors

Han S,Yang BZ,Kranzler HR,Liu X,Zhao H,Farrer LA,Boerwinkle E,Potash JB,Gelernter J

doi

10.1016/j.ajhg.2013.10.021

subject

Has Abstract

pub_date

2013-12-05 00:00:00

pages

1027-34

issue

6

eissn

0002-9297

issn

1537-6605

pii

S0002-9297(13)00478-3

journal_volume

93

pub_type

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