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

Am J Med Genet B Neuropsychiatr Genet. 2019 Jan;180(1):3-11. doi: 10.1002/ajmg.b.32692. Epub 2018 Nov 28.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Alcoholism / epidemiology
  • Alcoholism / genetics*
  • Alleles
  • Black or African American / genetics
  • Comorbidity
  • Ethanol / metabolism
  • Female
  • G(M2) Activator Protein / genetics
  • G(M2) Activator Protein / metabolism
  • Gene Frequency / genetics
  • Gene Regulatory Networks / genetics*
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study / methods
  • Humans
  • Male
  • Middle Aged
  • Nicotine / metabolism
  • Polymorphism, Single Nucleotide / genetics
  • Protein Interaction Maps / genetics
  • Risk Factors
  • Tobacco Use Disorder / epidemiology
  • Tobacco Use Disorder / genetics*
  • White People / genetics


  • G(M2) Activator Protein
  • Ethanol
  • Nicotine