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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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.
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. (PDF 581 kb)
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