Genetic variation in human NPY expression affects stress response and emotion

• Published in: Nature Vol. 452; no. 7190; pp. 997 - 1001
• Main Authors: Zhou, Zhifeng, Zhu, Guanshan, Hariri, Ahmad R., Enoch, Mary-Anne, Scott, David, Sinha, Rajita, Virkkunen, Matti, Mash, Deborah C., Lipsky, Robert H., Hu, Xian-Zhang, Hodgkinson, Colin A., Xu, Ke, Buzas, Beata, Yuan, Qiaoping, Shen, Pei-Hong, Ferrell, Robert E., Manuck, Stephen B., Brown, Sarah M., Hauger, Richard L., Stohler, Christian S., Zubieta, Jon-Kar, Goldman, David
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.04.2008; Nature Publishing; Nature Publishing Group
• Subjects: Alleles; Anxiety - genetics; Anxiety Disorders - genetics; Behavior; Biological and medical sciences; Brain; Brain - metabolism; Brain - physiology; Brain - physiopathology; Emotions; Facial Expression; Finland - ethnology; Gene Expression Regulation - genetics; Genes; Genetic diversity; Genetic Variation - genetics; Haplotypes - genetics; Humanities and Social Sciences; Humans; letter; Lymphocytes - metabolism; Magnetic Resonance Imaging; Male; Medical imaging; Medical sciences; multidisciplinary; Neurology; Neuropeptide Y - blood; Neuropeptide Y - genetics; Neuropharmacology; Opioid Peptides - metabolism; Pain - genetics; Peptides; Pharmacology. Drug treatments; Polymorphism, Single Nucleotide - genetics; Psycholeptics: tranquillizer, neuroleptic; Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Regression analysis; RNA, Messenger - genetics; RNA, Messenger - metabolism; Science; Science (multidisciplinary); Stress, Physiological - genetics; Stress, Physiological - psychology; United States - ethnology; Variance analysis; White People - genetics; United States; Finland; Human; Neuropeptide Y; Affect affectivity; Genetic variability; Psychotropic; Central nervous system; Basal ganglion; Emotion emotionality; Limbic system; Genetic determinism; Stress; Encephalon; Phenotype; Treatment; Interindividual comparison; Arousal; Genetics; Behavior; Release
• ISSN: 0028-0836; 1476-4687; 1476-4687; 1476-4679
• DOI: 10.1038/nature06858

The Y factor 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 anxiolytic 1 , 2 and its release is induced by stress 3 . 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 memories 4 , 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.