Dopamine genes and nicotine dependence in treatment-seeking and community smokers.
We utilized a cohort of 828 treatment-seeking self-identified white cigarette smokers (50% female) to rank candidate gene single nucleotide polymorphisms (SNPs) associated with the Fagerström Test for Nicotine Dependence (FTND), a measure of nicotine dependence which assesses quantity of cigarettes smoked and time- and place-dependent characteristics of the respondent's smoking behavior. A total of 1123 SNPs at 55 autosomal candidate genes, nicotinic acetylcholine receptors and genes involved in dopaminergic function, were tested for association to baseline FTND scores adjusted for age, depression, education, sex, and study site. SNP P-values were adjusted for the number of transmission models, the number of SNPs tested per candidate gene, and their intragenic correlation. DRD2, SLC6A3, and NR4A2 SNPs with adjusted P-values <0.10 were considered sufficiently noteworthy to justify further genetic, bioinformatic, and literature analyses. Each independent signal among the top-ranked SNPs accounted for approximately 1% of the FTND variance in this sample. The DRD2 SNP appears to represent a novel association with nicotine dependence. The SLC6A3 SNPs have previously been shown to be associated with SLC6A3 transcription or dopamine transporter density in vitro, in vivo, and ex vivo. Analysis of SLC6A3 and NR4A2 SNPs identified a statistically significant gene-gene interaction (P=0.001), consistent with in vitro evidence that the NR4A2 protein product (NURR1) regulates SLC6A3 transcription. A community cohort of N=175 multiplex ever-smoking pedigrees (N=423 ever smokers) provided nominal evidence for association with the FTND at these top ranked SNPs, uncorrected for multiple comparisons.
Bergen
Andrew W
AW
Center for Health Sciences, SRI International, Menlo Park, CA 94025, USA. andrew.bergen@sri.com
Conti
David V
DV
Van Den Berg
David
D
Lee
Wonho
W
Liu
Jinghua
J
Li
Dalin
D
Guo
Nan
N
Mi
Huaiyu
H
Thomas
Paul D
PD
Lessov-Schlaggar
Christina N
CN
Krasnow
Ruth
R
He
Yungang
Y
Nishita
Denise
D
Jiang
Ruhong
R
McClure
Jennifer B
JB
Tildesley
Elizabeth
E
Hops
Hyman
H
Tyndale
Rachel F
RF
Benowitz
Neal L
NL
Lerman
Caryn
C
Swan
Gary E
GE
D000328:Adult; D000704:Analysis of Variance; D016642:Bupropion / Q000627:therapeutic use; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000235:genetics; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics*; D018765:Dopamine Uptake Inhibitors / Q000627:therapeutic use; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D050637:Receptors, Dopamine D3 / Q000235:genetics*; D012111:Residence Characteristics; D012907:Smoking / Q000235:genetics*; D014029:Tobacco Use Disorder / Q000188:drug therapy / Q000235:genetics* / Q000523:psychology; D014157:Transcription Factors / Q000235:genetics; D044465:White People / Q000235:genetics
D004268:DNA-Binding Proteins; C493593:DRD3 protein, human; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; C539882:NR4A2 protein, human; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D050637:Receptors, Dopamine D3; C493214:SLC6A3 protein, human; D014157:Transcription Factors; D016642:Bupropion