A genetically modulated, intrinsic cingulate circuit supports human nicotine addiction

L. Elliot Hong, Colin A. Hodgkinson, Yihong Yang, Hemalatha Sampath, Thomas J. Ross, Brittany Buchholz, Betty Jo Salmeron, Vibhuti Srivastava, Gunvant K. Thaker, David Goldman, Elliot A. Stein

Research output: Contribution to journalArticlepeer-review

121 Scopus citations


Whole-genome searches have identified nicotinic acetylcholine receptor α5-α3-β4 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 α5 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.

Original languageEnglish (US)
Pages (from-to)13509-13514
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number30
StatePublished - Jul 27 2010
Externally publishedYes


  • Functional connectivity
  • Genetics
  • Imaging
  • Smoking
  • nAChR

ASJC Scopus subject areas

  • General


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