P2RX7, a gene coding for a purinergic ligand-gated ion channel, is associated with major depressive disorder

Abstract

The P2RX7 gene is located within a region on chromosome 12q24.31 that has been identified as a susceptibility locus for affective disorders by linkage and association studies. P2RX7 is a purinergic ATP-binding calcium channel expressed in neurons as well as in microglial cells in various brain regions. We investigated 29 single nucleotide polymorphisms (SNPs) within the P2RX7 gene and adjacent genes in a sample of 1000 German Caucasian patients suffering from recurrent major depressive disorder (MDD). These were contrasted with diagnosed healthy Caucasian controls from the same population (n=1029). A non-synonymous coding SNP in the P2RX7 gene (rs2230912), previously found to be associated with bipolar disorder, was significantly associated (P=0.0019) with MDD. This polymorphism results in an amino acid exchange in the C-terminal cytosolic domain of the P2RX7 channel protein, suggesting that the observed P2RX7 polymorphism might play a causal role in the development of depression.

Case–control studies show that a non-conservative amino-acid change from a glutamine to arginine in the P2RX7 purinergic receptor protein is associated with both bipolar- and unipolar-affective disorders

“…Data for association between rs2230912 (P2RX7-E13A) and bipolar disorder was published in the first P2RX7 bipolar study 15 and also in a follow-up study on major depression. 16 The minor allele (G) in all three studies was found at an increased frequency in patients with mood disorder. Table 4 shows the results of a combined analysis of data for rs2230912 from Barden et al 15 and Lucae et al 16 combined with the UCL bipolar data for 3586 individuals.…”

“…16 The minor allele (G) in all three studies was found at an increased frequency in patients with mood disorder. Table 4 shows the results of a combined analysis of data for rs2230912 from Barden et al 15 and Lucae et al 16 combined with the UCL bipolar data for 3586 individuals. This analysis showed significant allelic association (P = 0.0025) and genotypic association (P = 0.0005).…”

“…15 rs2230912 has shown some evidence for association with major depression (genotypic association P = 0.0019; allelic association P = 0.061). 16 Another region of 150 kb which is distant from P2RX7, in the12q23-24 region, encompassing the genes CUX2 and FLJ32356 has been studied in a UK case-control sample. 17 Allelic association was identified with one microsatellite marker (P = 0.0016), two single nucleotide polymorphisms (SNPs) (rs3847953, P = 0.002; rs933399, P = 0.004) and an insertion/deletion with putative functional relevance (P = 0.005).…”

Profiling of behavioral changes and hippocampal gene expression in mice chronically treated with the SSRI paroxetine

“…Some interesting novel drug targets came up by these strategies (e.g. Lucae et al 2006;McQuilin et al 2008), but overall, the success in using genotype information for identification of valid drug targets is limited so far. The main reason for this disenchantment is that the genotype provides little information about changes in gene activity following a cellular challenge.…”

Biological Alterations in Depression

“…Within this putative region lies the purinergic ATPbinding calcium channel gene (P2X7). A non-synonymous coding SNP within P2X7 (Gln460Arg) is associated with MDD risk (Lucae et al, 2006). P2X7 protein is required for IL-1 (interleukin-1) processing and secretion (Ferrari et al, 2006), highlighting the potential role of immune function in depressive behavior.…”