1. Laboratory of Neurogenetics, NIAAA, NIH, Bethesda, Maryland 20892, USA
2. Departments of Psychiatry, Human Genetics, and Psychology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA
3. Departments of Psychiatry and Radiology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA
4. Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06510, USA
5. Department of Psychiatry, University of Helsinki, 00014, Helsinki, Finland
6. Department of Neurology, University of Miami School of Medicine, Miami, Florida 33124, USA
7. Department of Psychiatry, San Diego VA Healthcare System and University of California, San Diego, California 92161, USA
8. School of Dentistry, University of Maryland, Baltimore, Maryland 21201, USA
9. These authors contributed equally to this work.
10. Present address: Innovation Centre China, AstraZeneca Global R&D, Shanghai 201203, China.

Correspondence to: David Goldman¹ Correspondence and requests for materials should be addressed to D.G. (Email: davidgoldman@mail.nih.gov).

Abstract

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 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 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.

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