title: Emotion processing, major depression, and functional genetic variation of neuropeptide Y.
abstract: BACKGROUND
  Despite recent progress in describing the common neural circuitry of emotion and stress processing, the bases of individual variation are less well understood. Genetic variants that underlie psychiatric disease have proven particularly difficult to elucidate. Functional genetic variation of neuropeptide Y (NPY) was recently identified as a source of individual differences in emotion. Low NPY levels have been reported in major depressive disorder (MDD).
  
  
  OBJECTIVE
  To determine whether low-expression NPY genotypes are associated with negative emotional processing at 3 levels of analysis.
  
  
  METHODS
  Cross-sectional, case-control study.
  
  
  METHODS
  Academic medical center.
  
  
  METHODS
  Among 44 individuals with MDD and 137 healthy controls, 152 (84%) had an NPY genotype classified as low, intermediate, or high expression according to previously established haplotype-based expression data.
  
  
  METHODS
  Healthy subjects participated in functional magnetic resonance imaging while viewing negative (vs neutral) words (n = 58) and rated positive and negative affect during a pain-stress challenge (n = 78). Genotype distribution was compared between 113 control subjects and 39 subjects with MDD.
  
  
  RESULTS
  Among healthy individuals, negatively valenced words activated the medial prefrontal cortex. Activation within this region was inversely related to genotype-predicted NPY expression (P = .03). Whole-brain regression of responses to negative words showed that the rostral anterior cingulate cortex activated in the low-expression group and deactivated in the high-expression group (P < .05). During the stress challenge, individuals with low-expression NPY genotypes reported more negative affective experience before and after pain (P = .002). Low-expression NPY genotypes were overrepresented in subjects with MDD after controlling for age and sex (P = .004). Population stratification did not account for the results.
  
  
  CONCLUSIONS
  These findings support a model in which NPY genetic variation predisposes certain individuals to low NPY expression, thereby increasing neural responsivity to negative stimuli within key affective circuit elements, including the medial prefrontal and anterior cingulate cortices. These genetically influenced neural response patterns appear to mediate risk for some forms of MDD.
authors.affiliation: Molecular and Behavioral Neuroscience Institute, University of Michigan, 205 Zina Pitcher Pl, Ann Arbor, MI 48109-5720, USA. bmickey@umich.edu
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Mickey
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Zhou
authors.forename: Mary M
authors.initials: MM
authors.lastname: Heitzeg
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Heinz
authors.forename: Colin A
authors.initials: CA
authors.lastname: Hodgkinson
authors.forename: David T
authors.initials: DT
authors.lastname: Hsu
authors.forename: Scott A
authors.initials: SA
authors.lastname: Langenecker
authors.forename: Tiffany M
authors.initials: TM
authors.lastname: Love
authors.forename: Marta
authors.initials: M
authors.lastname: Peciña
authors.forename: Tal
authors.initials: T
authors.lastname: Shafir
authors.forename: Christian S
authors.initials: CS
authors.lastname: Stohler
authors.forename: David
authors.initials: D
authors.lastname: Goldman
authors.forename: Jon-Kar
authors.initials: JK
authors.lastname: Zubieta
mesh_terms: D000328:Adult; D000679:Amygdala / Q000503:physiopathology; D001143:Arousal / Q000502:physiology; D001921:Brain / Q000503:physiopathology*; D001931:Brain Mapping; D016022:Case-Control Studies; D003430:Cross-Sectional Studies; D003865:Major Depressive Disorder / Q000235:genetics* / Q000503:physiopathology* / Q000523:psychology; D004644:Emotions / Q000502:physiology*; D005260:Female; D015870:Gene Expression / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006179:Gyrus Cinguli / Q000503:physiopathology; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009415:Nerve Net / Q000503:physiopathology; D009478:Neuropeptide Y / Q000235:genetics*; D010146:Pain / Q000503:physiopathology / Q000523:psychology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017397:Prefrontal Cortex / Q000503:physiopathology; D012016:Reference Values; D055815:Young Adult
chemical_list: D009478:Neuropeptide Y