Genetic variation in human NPY expression affects stress response and emotion.
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.
Zhou
Zhifeng
Z
Laboratory of Neurogenetics, NIAAA, NIH, Bethesda, Maryland 20892, USA.
Zhu
Guanshan
G
Hariri
Ahmad R
AR
Enoch
Mary-Anne
MA
Scott
David
D
Sinha
Rajita
R
Virkkunen
Matti
M
Mash
Deborah C
DC
Lipsky
Robert H
RH
Hu
Xian-Zhang
XZ
Hodgkinson
Colin A
CA
Xu
Ke
K
Buzas
Beata
B
Yuan
Qiaoping
Q
Shen
Pei-Hong
PH
Ferrell
Robert E
RE
Manuck
Stephen B
SB
Brown
Sarah M
SM
Hauger
Richard L
RL
Stohler
Christian S
CS
Zubieta
Jon-Kar
JK
Goldman
David
D
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
D009478:Neuropeptide Y; D018847:Opioid Peptides; D012333:RNA, Messenger