ADORA2A variation and adenosine A1 receptor availability in the human brain with a focus on anxiety-related brain regions: modulation by ADORA1 variation

Adenosine, its interacting A(1) and A(2A) receptors, and particularly the variant rs5751876 in the A(2A) gene ADORA2A have been shown to modulate anxiety, arousal, and sleep. In a pilot positron emission tomography (PET) study in healthy male subjects, we suggested an effect of rs5751876 on in vivo brain A(1) receptor (A(1)AR) availability. As female sex and adenosinergic/dopaminergic interaction partners might have an impact on this rs5751876 effect on A(1)AR availability, we aimed to (1) further investigate the pilot male-based findings in an independent, newly recruited cohort including women and (2) analyze potential modulation of this rs5751876 effect by additional adenosinergic/dopaminergic gene variation. Healthy volunteers (32/11 males/females) underwent phenotypic characterization including self-reported sleep and A(1)AR-specific quantitative PET. Rs5751876 and 31 gene variants of adenosine A(1), A(2A), A(2B), and A(3) receptors, adenosine deaminase, and dopamine D-2 receptor were genotyped. Multivariate analysis revealed an rs5751876 effect on A(1)AR availability (P=0.047), post hoc confirmed in 30 of 31 brain regions (false discovery rate (FDR) corrected P values<0.05), but statistically stronger in anxiety-related regions (e.g., amygdala, hippocampus). Additional effects of ADORA1 rs1874142 were identified; under its influence rs5751876 and rs5751876 x sleep had strengthened effects on A(1)AR availability (P-both<0.02; post hoc FDR-corrected Ps<0.05 for 29/30 regions, respectively). Our results support the relationship between rs5751876 and A(1)AR availability. Additional impact of rs1874142, together with rs5751876 and sleep, might be involved in regulating arousal and thus the development of mental disorders like anxiety disorders. The interplay of further detected suggestive ADORA2A x DRD2 interaction, however, necessitates larger future samples more comparable to magnetic resonance imaging (MRI)-based samples.