Analysis of single nucleotide polymorphisms in genes in the chromosome 12Q24.31 region points to P2RX7 as a susceptibility gene to bipolar affective disorder

Barden, Nicholas; Harvey, Mario; Gagné, Bernard; Shink, Éric; Tremblay, Monique; Raymond, Catherine; Labbé, Michel; Villeneuve, A; Rochette, Denis; Bordeleau, Lise; Stadler, H.; Holsboer, Florian; Müller‐Myhsok, Bertram

doi:10.1002/ajmg.b.30303

Cited by 194 publications

(152 citation statements)

References 62 publications

Supporting

Mentioning

138

Contrasting

Order By: Relevance

“…The 21 bp deletion in exon thirteen of P2RX7 15 was not observed in any of the bipolar disorder individuals. The data for six of the seven SNPs were in Hardy-Weinberg equilibrium (HWE) for the control samples.…”

Section: Resultsmentioning

confidence: 78%

“…No correction for multiple testing has been applied because the appropriate method for correcting these analyses is not clear. 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.…”

Section: Resultsmentioning

confidence: 99%

“…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).…”

Section: Resultsmentioning

confidence: 99%

“…Assays were designed for seven SNPs from the original Barden study rs208293 (P2RX7-I04B), rs208294 (P2RX7-E05A), rs504677 (P2RX7-I07E), rs1718119 (P2RX7-E11B), rs2230912 (P2RX7-E13A), rs11065501 (P2XR4-UTR3A) and rs3817190 (CAMKK2-E01B). 15 Two of these SNPs (rs7958311 (P2RX7-E08A) and rs2230911 (P2XR7E11C)) failed to give reliable genotypes and were abandoned. Genotyping was carried out by Kbiosciences (Kbiosciences, Hoddesdon, UK) using Kaspar (Kbiosciences).…”

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

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

et al. 2008

View full text Add to dashboard Cite

Three linkage studies of bipolar disorder have implicated chromosome 12q24.3 with lod scores of over 3.0 and several other linkage studies have found lods between 2 and 3. Fine mapping within the original chromosomal linkage regions has identified several loci that show association with bipolar disorder. One of these is the P2RX7 gene encoding a central nervous system-expressed purinergic receptor. A non-synonymous single nucleotide polymorphism, rs2230912 (P2RX7-E13A, G allele) and a microsatellite marker NBG6 were both previously found to be associated with bipolar disorder (P = 0.00071 and 0.008, respectively). rs2230912 has also been found to show association with unipolar depression. The effect of the polymorphism is non-conservative and results in a glutamine to arginine change (Gln460Arg), which is likely to affect P2RX7 dimerization and protein-protein interactions. We have confirmed the allelic associations between bipolar disorder and the markers rs2230912 (P2RX7-E13A, G allele, P = 0.043) and NBG6 (P = 0.010) in a London-based sample of 604 bipolar cases and 560 controls. When we combined these data with the published case-control studies of P2RX7 and mood disorder (3586 individuals) the association between rs2230912 (Gln460Arg) and affective disorders became more robust (P = 0.002). The increase in Gln460Arg was confined to heterozygotes rather than homozygotes suggesting a dominant effect (odds ratio 1.302, CI = 1.129-1.503). Although further research is needed to prove that the Gln460Arg change has an aetiological role, it is so far the most convincing mutation to have been found with a role for increasing susceptibility to bipolar and genetically related unipolar disorders.

show abstract

Section: Resultsmentioning

confidence: 78%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2008

View full text Add to dashboard Cite

show abstract

“…Another putative gain-of-function polymorphism described recently, the Q460R substitution, appears to enhance pore activity of the P2X 7 receptor [58]. Increasing evidence from genetic association studies have demonstrated that the polymorphisms of the P2X 7 gene are implicated in various diseases such as chronic lymphocytic leukemia, tuberculosis, bipolar affective disorders, and diabetes [60][61][62][63][64][65][66][67]. It has also been reported that the polymorphisms are related to clinical outcome in allogeneic stem cell transplantation and to fracture risk and the efficacy of hormone replacement therapy [28,68].…”

Section: Introductionmentioning

confidence: 99%

Identification and characterization of a novel variant of the human P2X7 receptor resulting in gain of function

Sun

Chu

Singh

et al. 2009

Purinergic Signalling

View full text Add to dashboard Cite

The P2X 7 receptor exhibits significant allelic polymorphism in humans, with both loss and gain of function variants potentially impacting on a variety of infectious and inflammatory disorders. At least five loss-offunction polymorphisms (G150R, R307Q, T357S, E496A, and I568N) and two gain-of-function polymorphisms (H155Y and Q460R) have been identified and characterized to date. In this study, we used RT-PCR cloning to isolate and characterize P2X 7 cDNA clones from human PBMCs and THP-1 cells. A previously unreported variant with substitutions of V80M and A166G was identified. When expressed in HEK293 cells, this variant exhibited heightened sensitivity to the P2X 7 agonist (BzATP) relative to the most frequent allele, as shown by pore formation measured by fluorescent dye uptake into cells. Mutational analyses showed that A166G alteration was critical for the gain-offunction change, while V80M was not. Full-length variants with multiple previously identified nonsynonymous SNPs (H155Y, H270R, A348T, and E496A) were also identified. Distinct functional phenotypes of the P2X 7 variants or mutants constructed with multiple polymorphisms were observed. Gain-of-function variations (A166G or H155Y) could not rescue the loss-of-function E496A polymorphism. Synergistic effects of the gain-of-function variations were also observed. We also identified the A348T alteration as a weak gain-of-function variant. Thus, these results identify the new gain-of-function variant A166G and demonstrate that multiple-gene polymorphisms contribute to functional phenotypes of the human P2X 7 receptor.Furthermore, the results demonstrate that the C-terminal of the cysteine-rich domain 1 of P2X 7 is critical for regulation of P2X 7 -mediated pore formation.

show abstract

Novel Therapeutic Strategies for Bipolar Disorder

2010

View full text Add to dashboard Cite

Analysis of single nucleotide polymorphisms in genes in the chromosome 12Q24.31 region points to P2RX7 as a susceptibility gene to bipolar affective disorder

Cited by 194 publications

References 62 publications

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

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

Identification and characterization of a novel variant of the human P2X7 receptor resulting in gain of function

Novel Therapeutic Strategies for Bipolar Disorder

Contact Info

Product

Resources

About