GWAS and network analysis of co-occurring nicotine and alcohol dependence identifies significantly associated alleles and network

Authors:
Open Access
Publisher website
Google Scholar
Abstract
Alcohol dependence (AD) and nicotine dependence (ND) co‐occur frequently (AD+ND). We integrated SNP‐based, gene‐based, and protein–protein interaction network analyses to identify shared risk genes or gene subnetworks for AD+ND in African Americans (AAs, N = 2,094) and European Americans (EAs, N = 1,207). The DSM‐IV criterion counts for AD and ND were modeled as two dependent variables in a multivariate linear mixed model, and analyzed separately for the two populations. The most significant SNP was rs6579845 in EAs (p < 1.29 × 10−8) in GM2A, which encodes GM2 ganglioside activator, and is a cis‐expression quantitative locus that affects GM2A expression in blood and brain tissues. However, this SNP was not replicated in our another small sample (N = 678). We identified a subnetwork of 24 genes that contributed to the AD+ND criterion counts. In the gene‐set analysis for the subnetwork in an independent sample, the Study of Addiction: Genetics and Environment project (predominately EAs), these 24 genes as a set differed in AD+ND versus control subjects in EAs (p = .041). Functional enrichment analysis for this subnetwork revealed that the gene enrichment involved primarily nerve growth factor pathways, and cocaine and amphetamine addiction. In conclusion, we identified a genome‐wide significant variant at GM2A and a gene subnetwork underlying the genetic trait of shared AD+ND. These results increase our understanding of the shared (pleiotropic) genetic risk that underlies AD+ND.
Funding Information
  • National Institute of Mental Health (R01 DA1843, R01 DA12690, RC2 DA028909, R01 DA12849)
  • China Scholarship Council
  • National Institutes of Health (R01 AA11330, N01-HG-65403, P50 AA12870, R01 AA017535, K01 DA24758, R01 DA18432, R01 DA12690, RC2 DA028909, R01 DA12849)
  • U.S. Department of Veterans Affairs
  • US Veterans Affairs Connecticut and Veterans Affairs Philadelphia Mental Illness Research, Education and Clinical Centers

This publication has 51 references indexed in Scilit: