Rapid cycling (RC) is a severe form of bipolar disorder (BD) with an increased rate of episodes. Circadian disturbances are common in BD, and those with RC might be even more vulnerable.

To investigate if the P2RX7 gene would be involved in the circadian rhythm and in part thereby be implicated in RC.

Gene expression was analyzed in peripheral mononuclear cells (PBMCs) from healthy volunteers (n=8) at the sleep research center, University of California, Irvine Medical Center, USA. Swedish outpatients recruited from psychiatric clinics for BD, diagnosed with BD type 1(n=569; RC: n=121) and anonymous blood donor controls (n=1,044) was investigated in case-case and case-control SNP/haplotype association analyses.

P2RX7 RNA levels were dramatically increased during sleep deprivation in PBMCs from the healthy volunteers (p=2.3^*10^-9). The P2RX7 rs 2230912 _A allele was more common (OR=2.2, p=0.002) and the ACGTTT haplotype in P2RX7 containing the protective rs2230912_G allele was less common, among RC cases compared to nonRC bipolar patients and blood donor controls.

Sleep deprivation activates P2RX7 expression in healthy persons which suggests that P2RX7 is involved in, or downstream, circadian rhythm regulation. The putatively low-activity P2RX7 rs2230912 allele A variant was associated with RC in BD which supports earlier findings of P2RX7 associations to affective disorder.