title: Association of abstinence-induced alterations in working memory function and COMT genotype in smokers.
abstract: BACKGROUND
  The common methionine (met) for valine (val) at codon 158 (val(158)met) polymorphism in the catechol-O-methyltransferase (COMT) gene has been associated with nicotine dependence, alterations in executive cognitive function, and abstinence-induced working memory deficits in smokers.
  
  
  OBJECTIVE
  We sought to replicate the association of the COMT val allele with abstinence-induced alterations in working memory-related activity in task-positive (executive control) and task-negative (default mode network) regions.
  
  
  METHODS
  Forty smokers (20 val/val and 20 met/met) performed an N-back task while undergoing blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) on two separate occasions: following 72 h of confirmed abstinence and during smoking as usual. An independent sample of 48 smokers who completed the identical N-back task during fMRI in smoking vs. abstinence for another study was used as a validation sample.
  
  
  RESULTS
  Contrary to expectations, genotype by session interactions on BOLD signal in executive control regions (dorsolateral prefrontal cortex and dorsal cingulate/medial prefrontal cortex) revealed significant abstinence-induced reductions in the met/met group, but not the val/val group. Results also revealed that val/val smokers may exhibit less suppression of activation in task-negative regions such as the posterior cingulate cortex during abstinence (vs. smoking). These patterns were confirmed in the validation sample and in the whole-brain analysis, though the regions differed from the a priori regions of interest (ROIs) (e.g., precuneus, insula).
  
  
  CONCLUSIONS
  The COMT val(158)met polymorphism was associated with abstinence-related working memory deficits in two independent samples of smokers. However, inconsistencies compared to prior findings and across methods (ROI vs. whole-brain analysis) highlight the challenges inherent in reproducing results of imaging genetic studies in addiction.
authors.affiliation: Center for Interdisciplinary Research on Nicotine Addiction, Department of Psychiatry, University of Pennsylvania, 3535 Market Street, Suite 4100, Philadelphia, PA, 19104, USA, rlashare@mail.med.upenn.edu.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Ashare
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Valdez
authors.forename: Kosha
authors.initials: K
authors.lastname: Ruparel
authors.forename: Benjamin
authors.initials: B
authors.lastname: Albelda
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Hopson
authors.forename: John R
authors.initials: JR
authors.lastname: Keefe
authors.forename: James
authors.initials: J
authors.lastname: Loughead
authors.forename: Caryn
authors.initials: C
authors.lastname: Lerman
mesh_terms: D000328:Adult; D001921:Brain / Q000378:metabolism*; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D003071:Cognition; D056344:Executive Function / Q000502:physiology; D005260:Female; D005838:Genotype; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology*; D008875:Middle Aged; D010100:Oxygen / Q000097:blood; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D012907:Smoking / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: D002394:Catechol O-Methyltransferase; D010100:Oxygen