A genetically modulated, intrinsic cingulate circuit supports human nicotine addiction

Proc Natl Acad Sci U S A. 2010 Jul 27;107(30):13509-14. doi: 10.1073/pnas.1004745107. Epub 2010 Jul 19.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics
  • Adolescent
  • Adult
  • Amygdala / anatomy & histology
  • Amygdala / physiology
  • Basal Ganglia / anatomy & histology
  • Basal Ganglia / physiology
  • Brain Mapping
  • Female
  • Gene Frequency
  • Genotype
  • Gyrus Cinguli / anatomy & histology
  • Gyrus Cinguli / physiology*
  • Humans
  • Linkage Disequilibrium
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Nerve Tissue Proteins / genetics
  • Neural Pathways / anatomy & histology
  • Neural Pathways / metabolism
  • Neural Pathways / physiology
  • Polymorphism, Single Nucleotide*
  • Receptors, Nicotinic / genetics*
  • Smoking / genetics
  • Smoking / physiopathology
  • Smoking / psychology
  • Tobacco Use Disorder / genetics*
  • Tobacco Use Disorder / physiopathology*
  • Tobacco Use Disorder / psychology
  • Young Adult


  • 3' Untranslated Regions
  • CHRNA5 protein, human
  • Nerve Tissue Proteins
  • Receptors, Nicotinic
  • nicotinic receptor subunit alpha3