Animal studies have suggested neuropeptide S (NPS) and its receptor (NPSR) to be involved in the pathogenesis of anxiety-related behavior. In this study, a multilevel approach was applied to further elucidate the role of NPS in the etiology of human anxiety. The functional NPSR A/T (Asn¹°7Ile) variant (rs324981) was investigated for association with (1) panic disorder with and without agoraphobia in two large, independent case-control studies, (2) dimensional anxiety traits, (3) autonomic arousal level during a behavioral avoidance test and (4) brain activation correlates of anxiety-related emotional processing in panic disorder. The more active NPSR rs324981 T allele was found to be associated with panic disorder in the female subgroup of patients in both samples as well as in a meta-analytic approach. The T risk allele was further related to elevated anxiety sensitivity, increased heart rate and higher symptom reports during a behavioral avoidance test as well as decreased activity in the dorsolateral prefrontal, lateral orbitofrontal and anterior cingulate cortex during processing of fearful faces in patients with panic disorder. The present results provide converging evidence for a female-dominant role of NPSR gene variation in panic disorder potentially through heightened autonomic arousal and distorted processing of anxiety-relevant emotional stimuli.
Panic Disorder/genetics , Receptors, G-Protein-Coupled/genetics , Receptors, G-Protein-Coupled/physiology , Adult , Agoraphobia/complications , Agoraphobia/genetics , Agoraphobia/physiopathology , Alleles , Anxiety/genetics , Anxiety Disorders/genetics , Arousal/genetics , Arousal/physiology , Avoidance Learning/physiology , Case-Control Studies , Female , Functional Neuroimaging/methods , Functional Neuroimaging/psychology , Genotype , Heart Rate/physiology , Humans , Magnetic Resonance Imaging/methods , Magnetic Resonance Imaging/psychology , Male , Panic Disorder/complications , Panic Disorder/physiopathology , Polymorphism, Single Nucleotide/genetics , Sex Characteristics
The lifetime prevalence of panic disorder (PD) is up to 4% worldwide and there is substantial evidence that genetic factors contribute to the development of PD. Single-nucleotide polymorphisms (SNPs) in TMEM132D, identified in a whole-genome association study (GWAS), were found to be associated with PD in three independent samples, with a two-SNP haplotype associated in each of three samples in the same direction, and with a P-value of 1.2e-7 in the combined sample (909 cases and 915 controls). Independent SNPs in this gene were also associated with the severity of anxiety symptoms in patients affected by PD or panic attacks as well as in patients suffering from unipolar depression. Risk genotypes for PD were associated with higher TMEM132D mRNA expression levels in the frontal cortex. In parallel, using a mouse model of extremes in trait anxiety, we could further show that anxiety-related behavior was positively correlated with Tmem132d mRNA expression in the anterior cingulate cortex, central to the processing of anxiety/fear-related stimuli, and that in this animal model a Tmem132d SNP is associated with anxiety-related behavior in an F2 panel. TMEM132D may thus be an important new candidate gene for PD as well as more generally for anxiety-related behavior.
Anxiety/metabolism , Genetic Predisposition to Disease/genetics , Membrane Proteins/metabolism , Polymorphism, Single Nucleotide/genetics , Adult , Animals , Anxiety/genetics , Anxiety/pathology , Anxiety/physiopathology , Disease Models, Animal , Female , Frontal Lobe/metabolism , Genome-Wide Association Study , Humans , Male , Membrane Proteins/genetics , Mice , Middle Aged , Phenotype , Psychiatric Status Rating Scales , RNA, Messenger/metabolism , Severity of Illness Index
Rgs2 (regulator of G-protein signalling 2) gene recently was reported as a quantitative trait gene for anxious behaviour in mice and male Rgs2 knockout mice have been shown to be more anxious than wildtype mice. Therefore we investigated four non-coding single nucleotide polymorphisms in a sample of 173 patients with panic disorder and 173 matched controls of German descent. At the genotype level all four SNPs were associated with panic disorder (p = 0.02-0.05). At the haplotype level the strongest association was observed for a haplotype containing SNP3 and SNP 4 (subgroup men and men with agoraphobia: p = 0.01 and 0.03). This points towards a functional polymorphism at the 3' end of the gene. Our results support the hypothesis that variations of the Rgs2 gene play a role also for the development of anxiety in humans.
Anxiety/genetics , Polymorphism, Single Nucleotide/genetics , RGS Proteins/genetics , Agoraphobia/complications , Agoraphobia/genetics , Agoraphobia/psychology , Anxiety/psychology , Case-Control Studies , Chromosomes, Human, Pair 1/genetics , DNA Primers , Humans , Linkage Disequilibrium , Odds Ratio , Panic Disorder/genetics , Panic Disorder/psychology , Psychiatric Status Rating Scales , Reverse Transcriptase Polymerase Chain Reaction
