CHRNA4 and ANKK1 Polymorphisms Influence Smoking-Induced Nicotinic Acetylcholine Receptor Upregulation.
Tobacco smoking leads to increased numbers of β2*-containing nicotinic acetylcholine receptors (β2*-nAChRs) throughout the brain, which return to nonsmoker levels over extended abstinence. The goal of the current study was to determine whether the degree of tobacco smoking-induced changes in β2*-nAChR availability is genetically influenced.



In this study, 113 European Americans participated in one or two [(123)I]5-IA-85380 single photon emission computed tomography (SPECT) brain scans. Smokers (n = 58) participated in one scan at 7-9 days of abstinence and those who remained abstinent (n = 27) were imaged again at 6-8 weeks of abstinence. Age- and sex-matched nonsmokers (n = 55) participated in one scan. Blood samples were collected for DNA analysis and genotyped for single nucleotide polymorphisms (SNPs) in the CHRNA4 and ANKK1 gene loci. β2*-nAChR availability was measured in the thalamus, striatum, cortical regions, and cerebellum.



The CHRNA4 SNP rs2236196 and ANKK1 SNP rs4938015 were associated with significantly higher cerebellar and cortical β2*-nAChR availability in smokers versus nonsmokers for specific genotypes. There were no significant differences by carrier status in the change in β2*-nAChR availability in smokers from 7-9 days to 6-8 weeks of abstinence.



This study provides evidence for genetic regulation of tobacco smoking-induced changes in β2*-nAChR availability and suggests that β2*-nAChR availability could be an endophenotype mediating influences of CHRNA4 variants on nicotine dependence. These results highlight individual differences in the neurochemistry of nicotine dependence and may suggest the need for individualized programs for smoking cessation.



This study demonstrates genetic regulation of smoking-induced changes in β2*-nAChRs throughout the brain and highlights the need for personalized programs for smoking cessation.
Department of Psychiatry, Yale University School of Medicine, New Haven, CT; Department of Radiology, Yale University School of Medicine, New Haven, CT;
Irina
I
Esterlis
Department of Radiology, Yale University School of Medicine, New Haven, CT;
Ansel T
AT
Hillmer
Department of Radiology, Yale University School of Medicine, New Haven, CT;
Frederic
F
Bois
Department of Psychiatry, Yale University School of Medicine, New Haven, CT;
Brian
B
Pittman
Department of Psychiatry, Yale University School of Medicine, New Haven, CT;
Erin
E
McGovern
Department of Psychiatry, Yale University School of Medicine, New Haven, CT;
Stephanie S
SS
O'Malley
Department of Psychiatry, Yale University School of Medicine, New Haven, CT;
Marina R
MR
Picciotto
Department of Psychiatry, Yale University School of Medicine, New Haven, CT; Department of Psychiatry, Veterans Affairs Connecticut Healthcare System, West Haven, CT.
Bao-Zhu
BZ
Yang
Department of Psychiatry, Yale University School of Medicine, New Haven, CT; Department of Psychiatry, Veterans Affairs Connecticut Healthcare System, West Haven, CT.
Joel
J
Gelernter
Department of Psychiatry, Yale University School of Medicine, New Haven, CT; Department of Radiology, Yale University School of Medicine, New Haven, CT; kelly.cosgrove@yale.edu.
Kelly P
KP
Cosgrove
D000328:Adult; D016022:Case-Control Studies; D003342:Corpus Striatum / Q000000981:diagnostic imaging* / Q000378:metabolism; D005260:Female; D006801:Humans; D007457:Iodine Radioisotopes; D008297:Male; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012907:Smoking / Q000503:physiopathology*; D016540:Smoking Cessation / Q000379:methods; D000074606:Smoking Prevention; D014029:Tobacco Use Disorder / Q000235:genetics; D015899:Tomography, Emission-Computed, Single-Photon; D015854:Up-Regulation; D044465:White People
D007457:Iodine Radioisotopes; D017346:Protein Serine-Threonine Kinases; D011978:Receptors, Nicotinic; C489948:ANKK1 protein, human