Evidence for Genetic Linkage Between a Polymorphism in the Adenosine 2A Receptor and Panic Disorder

Abstract

Data from clinical and behavioral pharmacological studies have implicated adenosine in anxiety behaviors, while genetic studies have suggested that adenosine receptors may be associated with panic disorder. We have undertaken an analysis of several DNA sequence variations in the adenosine 2A receptor (ADORA2A) in a large sample of panic disorder pedigrees. Individuals from 70 panic disorder pedigrees, and 83 child-parent 'trios', were genotyped at five single-nucleotide polymorphisms (SNPs) in and near the ADORA2A gene and were analyzed for genetic linkage and association. Linkage analysis revealed elevated LOD scores for a silent substitution (1083C/T, SNP-4) in the second coding exon. This SNP has been previously reported to be associated with panic disorder. We observed a maximal heterogeneity LOD score of 2.98 (y ¼ 0) under a recessive genetic model and narrow diagnostic model. Other SNPs showed no evidence for linkage. Association tests were not significant for any of the five ADORA2A SNPs. When SNP haplotypes were assessed in the triads with TRANSMIT, one 3-marker haplotype (SNPs 1, 4, 5) was nominally significantly associated with panic disorder (p ¼ 0.029). Pairwise estimations of linkage disequilibrium between the SNPs showed strong patterns of linkage disequilibrium across the ADORA2A locus. Analyses carried out by broadening the panic disorder phenotype to include agoraphobia continued to support linkage to ADORA2A. Our findings provide evidence for a susceptibility locus for panic disorder, and possibly including agoraphobia, either within the ADORA2A gene or in a nearby region of chromosome 22, and serves as the first successful candidate gene replication study in panic disorder.

Association between ADORA2A and DRD2 Polymorphisms and Caffeine-Induced Anxiety

“…Deckert et al (1998) found that PD patients had a higher prevalence of the 1976 T allele compared to controls. Hamilton et al (2004) also report an association between this locus and susceptibility to PD. Therefore, our data suggest that responses to 150 mg caffeine might be examined further to investigate A 2A receptor-mediated mechanisms of anxiety.…”

“…In this study, individuals with the T/T genotype of the ADORA2A SNP rs5751876 (1976C/T) reported greater anxiety after 150 mg caffeine compared to other genotypic groups. The same polymorphism has been linked to panic disorder (PD) (Deckert et al, 1998;Hamilton et al, 2004), suggesting that this variant confers a risk for anxiety states in general. Recently, we have also reported that individuals with the 1976T/T genotype also experience more anxiety after acute doses of the prototypic stimulant drug, D-amphetamine (Hohoff et al, 2005).…”

Anatomical Distribution of Nucleoside System in the Human Brain and Implications for Therapy

“…Nevertheless, the nucleoside system is expected to be a target for new drugs to treat mood disorders ) . Caffeine, a competitive antagonist of the A 1 and A 2A Rs (Fredholm et al 1999 ) , promotes anxious behavior both in animal models and humans (Klein et al 1991 ) , and A 2A R polymorphisms are associated with increased incidence of panic disorder and depression (Hamilton et al 2004 ;Lam et al 2005 ;Tsai et al 2006 ) . In addition, mice lacking A 1 or A 2A Rs demonstrate anxiogenic-like behaviors (Gimenez-Llort et al 2002 ;Johansson et al 2001 ;Ledent et al 1997 ) .…”

Adenosine A2A Receptors in the Amygdala Control Synaptic Plasticity and Contextual Fear Memory

“…Interestingly, the acute administration of caffeine disrupts fear memory (Corodimas et al, 2000) and A 2A R polymorphisms are associated with panic disorders (Deckert et al, 1998;Hamilton et al, 2004), but it is unknown whether A 2A Rs control fear memory and synaptic plasticity in amygdala circuits. Thus, we now explored the involvement of A 2A Rs in the control of synaptic plasticity in the amygdala and their possible role in the control of fear memory.…”