Genetic variation in human NPY expression affects stress response and emotion

Abstract

An individual's ability to deal with stress and anxiety — risk factors for many diseases — varies widely across human populations and the factors contributing to emotional resilience are complex. A study led by researchers at the National Institute on Alcohol Abuse and Alcoholism now points to inherited variations in the expression of the natural anxiolytic peptide neuropeptide Y in the brain as a factor in determining why some people can withstand stress better than others. Across human populations, individual ability to deal with stress and anxiety spans a wide range. The causes of emotional resilience are complex; this paper shows the contribution of genetic variance in expression of neuropeptide Y (NPY), an anxiolytic peptide released in emotion-related neural circuitry. Genetic variants were predictive of not only NPY levels, but also fMRI and PET activation in response to emotional stimuli and pain-induced stress. Understanding inter-individual differences in stress response requires the explanation of genetic influences at multiple phenotypic levels, including complex behaviours and the metabolic responses of brain regions to emotional stimuli. Neuropeptide Y (NPY) is anxiolytic1,2 and its release is induced by stress3. NPY is abundantly expressed in regions of the limbic system that are implicated in arousal and in the assignment of emotional valences to stimuli and memories4,5,6. Here we show that haplotype-driven NPY expression predicts brain responses to emotional and stress challenges and also inversely correlates with trait anxiety. NPY haplotypes predicted levels of NPY messenger RNA in post-mortem brain and lymphoblasts, and levels of plasma NPY. Lower haplotype-driven NPY expression predicted higher emotion-induced activation of the amygdala, as well as diminished resiliency as assessed by pain/stress-induced activations of endogenous opioid neurotransmission in various brain regions. A single nucleotide polymorphism (SNP rs16147) located in the promoter region alters NPY expression in vitro and seems to account for more than half of the variation in expression in vivo. These convergent findings are consistent with the function of NPY as an anxiolytic peptide and help to explain inter-individual variation in resiliency to stress, a risk factor for many diseases.