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

Abstract

Adenosine, its interacting A1 and A2A receptors, and particularly the variant rs5751876 in the A2A 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 A1 receptor (A1AR) availability. As female sex and adenosinergic/dopaminergic interaction partners might have an impact on this rs5751876 effect on A1AR 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 A1AR-specific quantitative PET. Rs5751876 and 31 gene variants of adenosine A1, A2A, A2B, and A3 receptors, adenosine deaminase, and dopamine D2 receptor were genotyped. Multivariate analysis revealed an rs5751876 effect on A1AR 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 × sleep had strengthened effects on A1AR availability (Pboth < 0.02; post hoc FDR-corrected Ps < 0.05 for 29/30 regions, respectively). Our results support the relationship between rs5751876 and A1AR 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 × DRD2 interaction, however, necessitates larger future samples more comparable to magnetic resonance imaging (MRI)-based samples.

Genetics and Cognitive Vulnerability to Sleep Deprivation in Healthy Subjects: Interaction of ADORA2A, TNF-α and COMT Polymorphisms

“…The ADORA2A locus is located on human chromosome 22 and contains a set of SNPs, the most studied being rs5751876 (formally designated as 1976C/T or 1083C/T) and other polymorphisms such as rs5751862 and rs2236624, which are in high linkage disequilibrium with the rs5751876 [46]. These SNPs were identified and associated with the corresponding haplotypes with different anxiety-related personality scores [46][47][48][49]. The rs5751876 SNP is a synonymous variant located on the exon 4 position, while the rs5751862 is located on the 5 promoter region; rs2298383 and rs3761422 are on 5 UTR, rs2236624 is intronic on 3-4, and rs4822492 is on 3 UTR.…”

Genomic-Analysis-Oriented Drug Repurposing in the Search for Novel Antidepressants

“…Another target gene that we identified in the present study was ADORA1 , which regulates various biological functions, including the mechanisms underlying sleep [ 101 , 102 ], and psychiatric disorders including depression [ 103 , 104 , 105 ]. ADORA1 activation has been found to induce antidepressant-like effects [ 106 , 107 ].…”

Thematic trends and knowledge structure on cognitive behavior therapy for insomnia: A bibliometric and visualization analysis

“…Anxiety disorders are the most common mental health disorder worldwide, with a prevalence of 25%, and people with anxiety disorders often experience poor sleep quality, and further exacerbate anxiety. Molecular imaging evidence also suggests that there are specific neurotransmitter mechanisms of sleep-wake regulation associated with anxiety ( 20 ). It is known that there is a benefit of CBTI not only for insomnia but also for comorbid anxiety disorder ( 20 ).…”

“…Molecular imaging evidence also suggests that there are specific neurotransmitter mechanisms of sleep-wake regulation associated with anxiety ( 20 ). It is known that there is a benefit of CBTI not only for insomnia but also for comorbid anxiety disorder ( 20 ). A report of ten studies examining the effect of CBTI on depressive outcomes in patients with co-occurring depression and insomnia reported that CBTI may be an appropriate stand-alone treatment for co-occurring depression and insomnia, or in combination with antidepressants ( 21 ).…”