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

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.

Keywords: alcohol dependence co-occurring nicotine dependence; genome-wide association studies; network analysis; pleiotropy.

Figure 1.

Regional Manhattan plot of the genomewide association analysis result for alcohol dependence co-occurring nicotine dependence in the European American sample. Significance of GWAS genotyped and imputed SNPs of the 400kb region in the chromosomal region of GM2A.

Figure 2.

Gene subnetwork constructed with five significant modules generated in AAs and EAs in the AD co-occurring with ND GWAS Data Sets. All of the genes involved in each of the five significant modules were pulled together and resulted in 24 genes after the overlapping genes were removed (Table S1). Gene subnetwork of these 24 genes was generated from the human protein-protein interaction (PPI) network; we used Cytoscape software (http://cytoscape.org/) to show the relationship between these genes.