P2RX7: expression responds to sleep deprivation and associates with rapid cycling in bipolar disorder type 1

Abstract

Context: Rapid cycling is a severe form of bipolar disorder with an increased rate of episodes that is particularly treatment-responsive to chronotherapy and stable sleep-wake cycles. We hypothesized that the P2RX7 gene would be affected by sleep deprivation and be implicated in rapid cycling.

Objectives: To assess whether P2RX7 expression is affected by total sleep deprivation and if variation in P2RX7 is associated with rapid cycling in bipolar patients.

Design: Gene expression analysis in peripheral blood mononuclear cells (PBMCs) from healthy volunteers and case-case and case-control SNP/haplotype association analyses in patients.

Participants: Healthy volunteers at the sleep research center, University of California, Irvine Medical Center (UCIMC), USA (n = 8) and Swedish outpatients recruited from specialized psychiatric clinics for bipolar disorder, diagnosed with bipolar disorder type 1 (n = 569; rapid cycling: n = 121) and anonymous blood donor controls (n = 1,044).

Results: P2RX7 RNA levels were significantly increased during sleep deprivation in PBMCs from healthy volunteers (p = 2.3*10(-9)). The P2RX7 rs2230912 _A allele was more common (OR = 2.2, p = 0.002) and the ACGTTT haplotype in P2RX7 (rs1718119 to rs1621388) containing the protective rs2230912_G allele (OR = 0.45-0.49, p = 0.003-0.005) was less common, among rapid cycling cases compared to non-rapid cycling bipolar patients and blood donor controls.

Conclusions: Sleep deprivation increased P2RX7 expression in healthy persons and the putatively low-activity P2RX7 rs2230912 allele A variant was associated with rapid cycling in bipolar disorder. This supports earlier findings of P2RX7 associations to affective disorder and is in agreement with that particularly rapid cycling patients have a more vulnerable diurnal system.

Figure 1. P2RX7 gene expression in peripheral blood mononuclear cells from healthy volunteers.

P2RX7 RNA expression was increased by sleep deprivation in men (filled diamonds) and women (open triangles). Blood draw (x-axis) was at 7 p.m. and thereafter once every 6 hours. Sleep deprivation was at time points #6, #7, #8 and #9. RNA levels are the normalized average of exon expression across the entire RefSeq transcript. Diamonds and triangles indicate mean and error bars indicate SEM.

Figure 2. The strength of linkage disequilibrium (LD) between pairs of SNPs in ABD controls for P2RX7.

The heavy-line frame shows suggested haplotype blocks. The numbers in the squares represent the pair-wise D′ value, empty squares stand for D′ = 1. Pink-red color indicates a pair-wise LOD≥2 with redness proportional to D′. White-blue square indicates LOD<2.