TY - JOUR
T1 - Integrating gwass and human protein interaction networks identifies a gene subnetwork underlying alcohol dependence
AU - Han, Shizhong
AU - Yang, Bao Zhu
AU - Kranzler, Henry R.
AU - Liu, Xiaoming
AU - Zhao, Hongyu
AU - Farrer, Lindsay A.
AU - Boerwinkle, Eric
AU - Potash, James B.
AU - Gelernter, Joel
N1 - Funding Information:
The authors are grateful to the volunteer families and individuals who participated in this research study. The authors would like to thank Peilin Jia for helping in the use of dmGWAS R package. The authors are indebted to the two anonymous reviewers for their constructive comments. This study was supported by the Alcoholic Beverage Medical Research Foundation (ABMRF) grant (S.H.). This study was also supported by National Institutes of Health grants R01 DA12690, R01 DA12849, RC2 DA028909, R01 DA18432, R01 AA11330, R01 AA017535, and K01 DA24758, and by the VA Connecticut REAP center, a VA MERIT grant, VA National Center for PTSD Research, and the VA Connecticut and VISN4 MIRECC Centers. Genotyping services for a part of the Yale-Penn GWAS were provided by the Center for Inherited Disease Research (CIDR) and Yale University (Center for Genome Analysis). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University (contract number N01-HG-65403). The SAGE, COGA, and OZ-ALC GWAS data sets in this study were obtained from dbGaP. Detailed funding and support information for these GWAS data sets are in Supplemental Acknowledgements . H.R.K. has been a paid consultant or advisory board member for Alkermes, Lilly, Lundbeck, Pfizer, and Roche and is a member of the Alcohol Clinical Trials Initiative (ACTIVE) of the American Society of Clinical Psychopharmacology, which is supported by AbbVie, Lilly, Lundbeck, and Pfizer.
PY - 2013/12/5
Y1 - 2013/12/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84890307080&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84890307080&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2013.10.021
DO - 10.1016/j.ajhg.2013.10.021
M3 - Article
C2 - 24268660
AN - SCOPUS:84890307080
SN - 0002-9297
VL - 93
SP - 1027
EP - 1034
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 6
ER -