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Genetic variation in human NPY expression affects stress response and emotion

Nature 452, 997–1001 (24 April 2008) | Download Citation

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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 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.

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References

  1. 1.

    , , , & Behavioral effects of neuropeptide Y receptor agonists in the elevated plus-maze and fear-potentiated startle procedures. Behav. Pharmacol. 6, 215–222 (1995)

  2. 2.

    , , & Centrally administered neuropeptide Y (NPY) produces anxiolytic-like effects in animal anxiety models. Psychopharmacology (Berl.) 98, 524–529 (1989)

  3. 3.

    , , & Behavioral and endocrine adaptation, and up-regulation of NPY expression in rat amygdala following repeated restraint stress. Neuroreport 10, 3003–3007 (1999)

  4. 4.

    et al. Neuropeptide Y distribution in human brain. Nature 306, 584–586 (1983)

  5. 5.

    et al. Neuropeptide Y distribution in the rat brain. Science 221, 877–879 (1983)

  6. 6.

    , & Neuropeptide Y—a novel brain peptide with structural similarities to peptide YY and pancreatic polypeptide. Nature 296, 659–660 (1982)

  7. 7.

    & Stress and the individual. Mechanisms leading to disease. Arch. Intern. Med. 153, 2093–2101 (1993)

  8. 8.

    Allostasis and allostatic load: implications for neuropsychopharmacology. Neuropsychopharmacology 22, 108–124 (2000)

  9. 9.

    , , , & Stress-induced cocaine craving and hypothalamic–pituitary–adrenal responses are predictive of cocaine relapse outcomes. Arch. Gen. Psychiatry 63, 324–331 (2006)

  10. 10.

    et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301, 386–389 (2003)

  11. 11.

    , & Meta-analysis of the association between a serotonin transporter promoter polymorphism (5-HTTLPR) and anxiety-related personality traits. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 127, 85–89 (2004)

  12. 12.

    et al. Serotonin transporter genetic variation and the response of the human amygdala. Science 297, 400–403 (2002)

  13. 13.

    et al. Amygdala–prefrontal coupling depends on a genetic variation of the serotonin transporter. Nature Neurosci. 8, 20–21 (2005)

  14. 14.

    et al. 5-HTTLPR polymorphism impacts human cingulate–amygdala interactions: a genetic susceptibility mechanism for depression. Nature Neurosci. 8, 828–834 (2005)

  15. 15.

    , , & Emotional conflict and neuroticism: personality-dependent activation in the amygdala and subgenual anterior cingulate. Behav. Neurosci. 121, 249–256 (2007)

  16. 16.

    , , , & Human amygdala responses during presentation of happy and neutral faces: correlations with state anxiety. Biol. Psychiatry 55, 897–903 (2004)

  17. 17.

    et al. Dopamine modulates the response of the human amygdala: a study in Parkinson’s disease. J. Neurosci. 22, 9099–9103 (2002)

  18. 18.

    et al. A susceptibility gene for affective disorders and the response of the human amygdala. Arch. Gen. Psychiatry 62, 146–152 (2005)

  19. 19.

    Stress and hippocampal plasticity. Annu. Rev. Neurosci. 22, 105–122 (1999)

  20. 20.

    et al. COMT val158met genotype affects μ-opioid neurotransmitter responses to a pain stressor. Science 299, 1240–1243 (2003)

  21. 21.

    et al. Regional mu opioid receptor regulation of sensory and affective dimensions of pain. Science 293, 311–315 (2001)

  22. 22.

    , & Deficit in attachment behavior in mice lacking the μ-opioid receptor gene. Science 304, 1983–1986 (2004)

  23. 23.

    & Organization of endogenous opiate and nonopiate pain control systems. Science 216, 1185–1192 (1982)

  24. 24.

    & Naloxone blocks ‘anxiolytic’ effects of neuropeptide Y. Peptides 22, 607–612 (2001)

  25. 25.

    , & Anti-nociceptive effect of neuropeptide Y in the nucleus accumbens of rats: an involvement of opioid receptors in the effect. Brain Res. 940, 69–78 (2002)

  26. 26.

    et al. Role of genotype in the cycle of violence in maltreated children. Science 297, 851–854 (2002)

  27. 27.

    , , & Informativeness of genetic markers for inference of ancestry. Am. J. Hum. Genet. 73, 1402–1422 (2003)

  28. 28.

    A cladistic analysis of phenotypic associations with haplotypes inferred from restriction endonuclease mapping or DNA sequencing. V. Analysis of case/control sampling designs: Alzheimer’s disease and the apoprotein E locus. Genetics 140, 403–409 (1995)

  29. 29.

    et al. Association of a leucine(7)-to-proline(7) polymorphism in the signal peptide of neuropeptide Y with high serum cholesterol and LDL cholesterol levels. Nature Med. 4, 1434–1437 (1998)

  30. 30.

    et al. Leucine 7 to proline 7 polymorphism in the neuropeptide Y gene is associated with retinopathy in type 2 diabetes. Exp. Clin. Endocrinol. Diabetes 108, 235–236 (2000)

  31. 31.

    , , , & Using ancestry-informative markers to define populations and detect population stratification. J. Psychopharmacol. 20, 19–26 (2006)

  32. 32.

    et al. Differential expression of human COMT alleles in brain and lymphoblasts detected by RT-coupled 5′ nuclease assay. Psychopharmacology (Berl.) 177, 178–184 (2004)

  33. 33.

    et al. Neuropeptide Y radio-immunoassay: characterization and application. Clin. Exp. Pharmacol. Physiol. 18, 825–833 (1991)

  34. 34.

    , , & Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005)

  35. 35.

    & A comparison of bayesian methods for haplotype reconstruction from population genotype data. Am. J. Hum. Genet. 73, 1162–1169 (2003)

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Acknowledgements

This work was supported by grants R01 DA 016423 to J.-K.Z., K01 MH072837 and a NARSAD Young Investigator Award to A.R.H., R01-AA13892, P50-DA16556 and K02-DA17232 to R.S., PO1 HL040962 and RO1 HL065137 to S.B.M., and R01 DE 15396 to C.S.S.

Author Contributions Z.Z. and G.Z. performed molecular biology and genetic analyses. A.R.H., R.E.F., S.B.M. and S.M.B. generated and analysed fMRI data. J.-K.Z., D.S. and C.S.S. generated and analysed PET data. R.S. and R.L.H. generated plasma NPY data. J.-K.Z., A.R.H., Z.Z., G.Z., D.S., M.V. and D.G. all contributed to conceptual issues. M.V. and D.G. were involved in the collection of the Finnish data set. D.C.M. provided post-mortem tissue samples. M.-A.E., R.H.L, X.-Z.H., C.H., K.X., B.B., Q.Y. and P.-H.S. contributed to data analysis. D.G. conceived and planned the study. Z.Z. and D.G. wrote the paper.

Author information

    • Zhifeng Zhou
    •  & Guanshan Zhu

    These authors contributed equally to this work.

    • Guanshan Zhu

    Present address: Innovation Centre China, AstraZeneca Global R&D, Shanghai 201203, China.

Affiliations

  1. Laboratory of Neurogenetics, NIAAA, NIH, Bethesda, Maryland 20892, USA

    • Zhifeng Zhou
    • , Guanshan Zhu
    • , Mary-Anne Enoch
    • , Robert H. Lipsky
    • , Xian-Zhang Hu
    • , Colin A. Hodgkinson
    • , Ke Xu
    • , Beata Buzas
    • , Qiaoping Yuan
    • , Pei-Hong Shen
    •  & David Goldman

  2. Departments of Psychiatry, Human Genetics, and Psychology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA

    • Ahmad R. Hariri
    • , Robert E. Ferrell
    • , Stephen B. Manuck
    •  & Sarah M. Brown

  3. Departments of Psychiatry and Radiology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA

    • David Scott
    •  & Jon-Kar Zubieta

  4. Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06510, USA

    • Rajita Sinha

  5. Department of Psychiatry, University of Helsinki, 00014, Helsinki, Finland

    • Matti Virkkunen

  6. Department of Neurology, University of Miami School of Medicine, Miami, Florida 33124, USA

    • Deborah C. Mash

  7. Department of Psychiatry, San Diego VA Healthcare System and University of California, San Diego, California 92161, USA

    • Richard L. Hauger

  8. School of Dentistry, University of Maryland, Baltimore, Maryland 21201, USA

    • Christian S. Stohler

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Correspondence to David Goldman.

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    Supplementary Information

    The supplementary Information contains Supplementary Figures 1 - 6 with Legends, Supplementary Tables 1 - 3, Supplementary Methods and additional references. The Supplementary Figures 1 - 6 and Supplementary Tables 1-2 provide supplementary results. Supplementary Table 3 contains the primer and probe sequences. The Supplementary Methods provide the details of the study subjects and the fMRI and PET methods.

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https://doi.org/10.1038/nature06858

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