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 postmortem 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.Reprints and permissions information is available at www.nature.com/reprints. Correspondence and requests for materials should be addressed to D.G. (E-mail: davidgoldman@mail.nih.gov). * These authors contributed equally to this work. † Present address: Innovation Centre China, AstraZeneca Global R&D, Shanghai 201203, China. Supplementary Fig. 1b). Five haplotypes (H1-H5) account for 93.8% of chromosomes in this block (Fig. 1a).We observed haplotype-driven NPY mRNA expression in postmortem brain (US Caucasians, Miami sample) by detecting the differential expression of alleles at single nucleotide polymorphism (SNP) rs5574 C/T, selected because of its high frequency and location in the transcript. Of these 28 samples, chosen because all were heterozygous for rs5574, 16 (57%) showed differential allele expression at an allele ratio of more than 1.2, in either direction. H1 and H4 were low-expression haplotypes, H2 was high, H3 was intermediate and H5 was unclassified because only two H1/H5 heterozygous brains were available (Fig. 1b). This expression-based functional classification is consistent with a cladistically based clustering of haplotypes, indicating that expression variation is linked to gene ancestry (Fig. 1a). The effects on expression of the more common H1, H2 and H3 haplotypes were verified in 47 lymphoblastoid cell lines derived from healthy Finnish men ( Fig. 1c) representing the six common diplotypes (72% of all diplotypes). On the basis of lymphoblast NPY mRNA levels, the expression value for each haplotype was calculated by regression analysis. Expression values for the six common diplotypes were well predicted under a co...

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Background-Associations between a functional polymorphism in the serotonin transporter gene and amygdala activation have been found in healthy, depressed, and anxious adults. This study explored these gene-brain associations in adolescents by examining predictive effects of serotonin transporter gene variants (S and L G allele carriers vs. L A allele homozygotes) and their interaction with diagnosis (healthy vs. patients) on amygdala responses to emotional faces.

A polymorphism of the human Brain Derived Neurotrophic Factor (BDNF) gene that produces a valine-to-methionine substitution at codon 66 (Val66Met), is linked to adult anxiety and mood disorders, possibly through effects on brain circuitry function. Associations between BDNF gene variants and brain activity have not been explored in anxious and depressed adolescents. The current study investigated the association between BDNF genotype and amygdala-hippocampal responses to emotional stimuli in adolescents with anxiety disorders and/or major depressive disorder (MDD) and in healthy adolescents. Twenty-seven unmedicated patients with acutelyimpairing current anxiety disorders and/or MDD and 31 healthy adolescents, matched on age, gender and IQ, rated their fear of fearful, angry, neutral and happy facial expressions during collection of fMRI data on the amygdala and hippocampus. Left and right amygdala and hippocampal responses were analyzed using Repeated-measures Analyses of Variance models, with Diagnosis (patients, healthy) and Genotype (Met-carriers, Val/Val homozygotes) as betweengroup factors and facial expression (fearful, angry, neutral, happy) as a within-subject factor. Significant effects of Diagnosis and Diagnosis-by-Genotype interactions (F's>4, p's<.05) characterized activations in amygdala and anterior hippocampal regions. Greater activations in patients than healthy adolescents were found. Critically, these hyperactivations were modulated by BDNF genotype: Met-carriers showed greater neural responses of emotional faces than Val/Val homozygotes in patients only. These data are first to demonstrate the contribution of BDNF gene variants to the neural correlates of adolescent anxiety and depression. Early "gene-brain" linkages may lay the foundation for longer-term patterns of neural dysfunction in affective disorders. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeuroimage. Author manuscript; available in PMC 2011 November 15. Anxiety and mood disorders are remarkably common (Kessler et al., 2007), posing huge costs to society (Bebbington, 2001;Rice and Miller, 1998). Anxiety disorders comprise a collection of syndromes characterized by exaggerated fear responses to perceived threats. Such threats extend to a wide range of situations in Generalized Anxiety Disorder (GAD), and to specific ones, such as social evaluation in Social Phobia (SoP) or separation from caregivers in Separation Anxiety Disorder (SAD). Major Depressive Disorder (MDD) is defined by episodes of low mood and/or anhedonia, and cognitive and vegeta...