A Genomewide Association Study of Nicotine and Alcohol Dependence in Australian and Dutch Populations

Persistent tobacco use and excessive alcohol consumption are major public health concerns worldwide. Both alcohol and nicotine dependence (AD, ND) are genetically influenced complex disorders that exhibit a high degree of comorbidity. To identify gene variants contributing to one or both of these addictions, we first conducted a pooling-based genomewide association study (GWAS) in an Australian population, using Illumina Infinium 1 M arrays. Allele frequency differences were compared between pooled DNA from case and control groups for: (1) AD, 1224 cases and 1162 controls; (2) ND, 1273 cases and 1113 controls; and (3) comorbid AD and ND, 599 cases and 488 controls. Secondly, we carried out a GWAS in independent samples from the Netherlands for AD and for ND. Thirdly, we performed a meta-analysis of the 10,000 most significant AD- and ND-related SNPs from the Australian and Dutch samples. In the Australian GWAS, one SNP achieved genomewide significance (p < 5 x 10(-8)) for ND (rs964170 in ARHGAP10 on chromosome 4, p = 4.43 x 10(-8)) and three others for comorbid AD/ND (rs7530302 near MARK1 on chromosome 1 (p = 1.90 x 10(-9)), rs1784300 near DDX6 on chromosome 11 (p = 2.60 x 10(-9)) and rs12882384 in KIAA1409 on chromosome 14 (p = 4.86 x 10(-18))). None of the SNPs achieved genomewide significance in the Australian/Dutch meta-analysis, but a gene network diagram based on the top-results revealed overrepresentation of genes coding for ion-channels and cell adhesion molecules. Further studies will be required before the detailed causes of comorbidity between AD and ND are understood.