title: Genetic variation in human NPY expression affects stress response and emotion.
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.
authors.affiliation: Laboratory of Neurogenetics, NIAAA, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Zhou
authors.forename: Guanshan
authors.initials: G
authors.lastname: Zhu
authors.forename: Ahmad R
authors.initials: AR
authors.lastname: Hariri
authors.forename: Mary-Anne
authors.initials: MA
authors.lastname: Enoch
authors.forename: David
authors.initials: D
authors.lastname: Scott
authors.forename: Rajita
authors.initials: R
authors.lastname: Sinha
authors.forename: Matti
authors.initials: M
authors.lastname: Virkkunen
authors.forename: Deborah C
authors.initials: DC
authors.lastname: Mash
authors.forename: Robert H
authors.initials: RH
authors.lastname: Lipsky
authors.forename: Xian-Zhang
authors.initials: XZ
authors.lastname: Hu
authors.forename: Colin A
authors.initials: CA
authors.lastname: Hodgkinson
authors.forename: Ke
authors.initials: K
authors.lastname: Xu
authors.forename: Beata
authors.initials: B
authors.lastname: Buzas
authors.forename: Qiaoping
authors.initials: Q
authors.lastname: Yuan
authors.forename: Pei-Hong
authors.initials: PH
authors.lastname: Shen
authors.forename: Robert E
authors.initials: RE
authors.lastname: Ferrell
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Manuck
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Brown
authors.forename: Richard L
authors.initials: RL
authors.lastname: Hauger
authors.forename: Christian S
authors.initials: CS
authors.lastname: Stohler
authors.forename: Jon-Kar
authors.initials: JK
authors.lastname: Zubieta
authors.forename: David
authors.initials: D
authors.lastname: Goldman
mesh_terms: D000483:Alleles; D001007:Anxiety / Q000235:genetics; D001008:Anxiety Disorders / Q000235:genetics; D001921:Brain / Q000378:metabolism* / Q000502:physiology / Q000503:physiopathology; D004644:Emotions; D005149:Facial Expression; D005387:Finland / Q000208:ethnology; D005786:Gene Expression Regulation / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D009478:Neuropeptide Y / Q000097:blood / Q000235:genetics*; D018847:Opioid Peptides / Q000378:metabolism; D010146:Pain / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological / Q000235:genetics* / Q000523:psychology; D014481:United States / Q000208:ethnology; D044465:White People / Q000235:genetics
chemical_list: D009478:Neuropeptide Y; D018847:Opioid Peptides; D012333:RNA, Messenger