Support for involvement of glutamate decarboxylase 1 and neuropeptide Y in anxiety susceptibility.
Genetic mapping efforts have identified putative susceptibility genes for human anxiety disorders. The most intensively studied genes are involved in neurotransmitter metabolism and signaling or stress response. In addition, neuropeptides and targets of anxiolytics have been examined. It has become apparent that gene × environment interactions may explain individual variation in stress resilience and predisposition to mental disorders. We aimed to replicate previous genetic findings in 16 putative anxiety susceptibility genes and further test whether they modulate the risk for developing an anxiety disorder in adulthood after childhood stress exposure. We tested 93 single-nucleotide polymorphisms (SNPs) for genetic association to anxiety disorders in the Finnish population-based Health 2000 sample (282 cases and 575 matched controls). In addition, we examined by logistic regression modeling whether the SNP genotypes modified the effect of the number of self-reported childhood adversities on anxiety disorder risk. The most significant evidence for association was observed in glutamate decarboxylase 1 (GAD1) with phobias (P = 0.0005). A subsequent meta-analysis (N = 1985) incorporating previously published findings supported involvement of a single GAD1 risk haplotype in determining susceptibility to a broad range of internalizing disorders (P = 0.0009). We additionally found that SNPs and haplotypes in neuropeptide Y (NPY) modified the effect of childhood adversities on anxiety susceptibility (P = 0.003). In conclusion, we provide further support for involvement of mainly GAD1, but also NPY in determining predisposition to anxiety disorders.
Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
Jonas
J
Donner
Tessa
T
Sipilä
Samuli
S
Ripatti
Laura
L
Kananen
Xiangning
X
Chen
Kenneth S
KS
Kendler
Jouko
J
Lönnqvist
Sami
S
Pirkola
John M
JM
Hettema
Iiris
I
Hovatta
D000328:Adult; D001007:Anxiety / Q000235:genetics*; D001483:Base Sequence; D002648:Child; D002649:Child Abuse / Q000523:psychology; D003710:Demography; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D015894:Genome, Human / Q000235:genetics; D005968:Glutamate Decarboxylase / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D008969:Molecular Sequence Data; D009478:Neuropeptide Y / Q000235:genetics*; D010641:Phenotype; D010698:Phobic Disorders / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
D009478:Neuropeptide Y; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1