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 1M 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(-8))). 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.
Lind
Penelope A
PA
Genetic Epidemiology, Queensland Institute of Medical Research, Brisbane, Australia. penelope.lind@qimr.edu.au
Macgregor
Stuart
S
Vink
Jacqueline M
JM
Pergadia
Michele L
ML
Hansell
Narelle K
NK
de Moor
Marleen H M
MH
Smit
August B
AB
Hottenga
Jouke-Jan
JJ
Richter
Melinda M
MM
Heath
Andrew C
AC
Martin
Nicholas G
NG
Willemsen
Gonneke
G
de Geus
Eco J C
EJ
Vogelzangs
Nicole
N
Penninx
Brenda W
BW
Whitfield
John B
JB
Montgomery
Grant W
GW
Boomsma
Dorret I
DI
Madden
Pamela A F
PA
D000328:Adult; D000368:Aged; D000437:Alcoholism / Q000453:epidemiology / Q000235:genetics*; D001315:Australia / Q000453:epidemiology; D016022:Case-Control Studies; D053487:DEAD-box RNA Helicases / Q000235:genetics; D004200:Diseases in Twins / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D009426:Netherlands / Q000453:epidemiology; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012042:Registries; D014029:Tobacco Use Disorder / Q000453:epidemiology / Q000235:genetics*; D020742:rhoA GTP-Binding Protein
C486050:ARHGAP10 protein, human; D020690:GTPase-Activating Proteins; D011518:Proto-Oncogene Proteins; C105547:MARK1 protein, human; D017346:Protein Serine-Threonine Kinases; C094683:DDX6 protein, human; D053487:DEAD-box RNA Helicases; D020742:rhoA GTP-Binding Protein