A genetically modulated, intrinsic cingulate circuit supports human nicotine addiction.
Whole-genome searches have identified nicotinic acetylcholine receptor alpha5-alpha3-beta4 subunit gene variants that are associated with smoking. How genes support this addictive and high-risk behavior through their expression in the brain remains poorly understood. Here we show that a key alpha5 gene variant Asp398Asn is associated with a dorsal anterior cingulate-ventral striatum/extended amygdala circuit, such that the "risk allele" decreases the intrinsic resting functional connectivity strength in this circuit. Importantly, this effect is observed independently in nonsmokers and smokers, although the circuit strength distinguishes smokers from nonsmokers, predicts addiction severity in smokers, and is not secondary to smoking per se, thus representing a trait-like circuitry biomarker. This same circuit is further impaired in people with mental illnesses, who have the highest rate of smoking. Identifying where and how brain circuits link genes to smoking provides practical neural circuitry targets for new treatment development.
Hong
L Elliot
LE
Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD 21228, USA. ehong@mprc.umaryland.edu
Hodgkinson
Colin A
CA
Yang
Yihong
Y
Sampath
Hemalatha
H
Ross
Thomas J
TJ
Buchholz
Brittany
B
Salmeron
Betty Jo
BJ
Srivastava
Vibhuti
V
Thaker
Gunvant K
GK
Goldman
David
D
Stein
Elliot A
EA
D020413:3' Untranslated Regions / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000679:Amygdala / Q000033:anatomy & histology / Q000502:physiology; D001479:Basal Ganglia / Q000033:anatomy & histology / Q000502:physiology; D001931:Brain Mapping; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006179:Gyrus Cinguli / Q000033:anatomy & histology / Q000502:physiology*; D006801:Humans; D015810:Linkage Disequilibrium; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics; D009434:Neural Pathways / Q000033:anatomy & histology / Q000378:metabolism / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D011978:Receptors, Nicotinic / Q000235:genetics*; D012907:Smoking / Q000235:genetics / Q000503:physiopathology / Q000523:psychology; D014029:Tobacco Use Disorder / Q000235:genetics* / Q000503:physiopathology* / Q000523:psychology; D055815:Young Adult
D020413:3' Untranslated Regions; D009419:Nerve Tissue Proteins; D011978:Receptors, Nicotinic; C447158:CHRNA5 protein, human