Genetic variation in human NPY expression affects stress response and emotion - PubMed (original) (raw)

. 2008 Apr 24;452(7190):997-1001.

doi: 10.1038/nature06858. Epub 2008 Apr 2.

Guanshan Zhu, Ahmad R Hariri, Mary-Anne Enoch, David Scott, Rajita Sinha, Matti Virkkunen, Deborah C Mash, Robert H Lipsky, Xian-Zhang Hu, Colin A Hodgkinson, Ke Xu, Beata Buzas, Qiaoping Yuan, Pei-Hong Shen, Robert E Ferrell, Stephen B Manuck, Sarah M Brown, Richard L Hauger, Christian S Stohler, Jon-Kar Zubieta, David Goldman

Affiliations

Genetic variation in human NPY expression affects stress response and emotion

Zhifeng Zhou et al. Nature. 2008.

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 and its release is induced by stress. 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. 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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Figures

Figure 1

Figure 1. Haplotype-predicted NPY expression in brain, lymphoblasts and plasma

aConfiguration, frequencies (right) and cladistic clustering (left) of major NPY haplotypes (H1, H2, H3, H4 and H5; frequency more than 1%) in Finnish Caucasians (n = 516). b, Differential allele expression of NPY mRNA showing allelic ratio (log2(C/T)) of rs5574 in 28 heterozygous human post-mortem cerebella (Miami sample) grouped according to diplotypes (columns 2–5, means ± s.d.) to infer expression levels of H2, H3, H4 and H5 relative to H1 (the T allele is found only within H1, as shown in a). Diplotypes are compared using a two-tailed _t_-test. Column 1 presents all samples; column 6 shows controls for allelic amplification efficiency. c, Expression levels of the six common diplotypes in 47 lymphoblastoid cell lines derived from healthy Finnish Caucasians. Expression values of the three major haplotypes (H1, H2 and H3) were calculated from observed diplotype values (points and error bars show means ± s.e.m.) by multiple regression and were used to predict diplotype values (bars) under a co-dominant model (see Supplementary Fig. 2 for details, including fit to model). Diplotypes were grouped as low (LL), intermediate (LH) or high (HH) in expression. Numbers above columns are n. d, Diplotype-predicted plasma NPY levels (means ± s.e.m., standardized with Z scores; New Haven sample) in controls (black diamonds; LL, n = 16; LH, n = 113; HH, n = 39) and alcoholic patients (grey squares; LL, n = 29; LH, n = 72; HH, n = 27). P values were calculated by regression analysis.

Figure 2

Figure 2. Effect of diplotype-predicted NPY mRNA expression on fMRI-measured amygdala and hippocampal activation in response to threat-related facial expressions

Top: statistical parametric maps representing NPY diplotype-biased (LL > LH > HH) mean right dorsal amygdala (x = 16, y = −8, z = −14, 64 voxels, t = 2.82, P = 0.003) and right hippocampal (x = 24, y = −20, z = −12, 132 voxels, t = 2.56, P = 0.006) activation is shown overlaid on an average sagittal and coronal MRI. Bottom: right amygdala (black diamonds) and hippocampal (grey squares) activities (means and s.e.m.) from clusters grouped by NPY diplotypes.

Figure 3

Figure 3. Effect of diplotype-predicted NPY mRNA expression on pain/stress-induced μ-opioid system activation

Activation (means ± s.e.m.) measured by the percentage change in the μ-opioid receptor binding potential (BP) among the NPY diplotypes (LL, n = 8; LH, n = 21; HH, n = 6) are shown in the dorsomedial prefrontal (dmPFC) and posterior insular (pINS) cortices, ventrolateral thalamus (vlTHA), ventral putamen (PUT) and caudate (CAU) nuclei, nucleus accumbens (NAC) and ventral amygdala (AMY; Supplementary Table 1). Z scores represented by the pseudocolour scale (left) are superimposed on an anatomically standardized MRI image. See also Supplementary Table 1 for details of the localization and statistics.

Figure 4

Figure 4. Correlations of diplotype-predicted NPY mRNA expression with TPQ trait anxiety and anxiety disorders in Finnish Caucasians

a, Bivariate regression of HA1 and HA2 scores (means and s.e.m.) and diplotype-predicted expression values in 137 healthy subjects (left to right: H1/H1, n = 33; H1/H3, n = 35; H3/H3, n = 5; H1/H2, n = 39; H2/H3, n = 15; H2/H2, n = 10). b, Diplotype-predicted NPY mRNA levels (means and s.e.m.) of n = 137 healthy controls and n = 18 anxiety patients by a two-tailed _t_-test (means ± s.e.m. for HA1 and HA2 are also shown). At the top right is a histogram comparing the numbers of controls and anxiety patients within each of the six diplotypes.

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