Emotion Processing, Major Depression, and Functional Genetic Variation of Neuropeptide Y

Context: 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. Design: Cross-sectional, case-control study. Setting: Academic medical center. Participants: 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. Main Outcome Measures: 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.