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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

Molecular Psychiatry volume 14, pages 614–620 (2009)Cite this article

Abstract

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.

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Acknowledgements

We are very grateful to the Manic Depression Fellowship (MDF) and their members for their generous contribution to the collection of patient samples. We also thank several NHS clinicians for their help in collecting samples. The research was funded by project grants G9623693N and G0500791 from the UK Medical Research Council, the Neuroscience Research Charitable Trust and by a research lectureship from the Priory Hospitals.

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  1. Department of Mental Health Sciences, Molecular Psychiatry Laboratory, Windeyer Institute of Medical Sciences, Royal Free and University College Medical School, University College London, London, UK

    A McQuillin, N J Bass, K Choudhury, V Puri, M Kosmin, J Lawrence & H M D Gurling

  2. Academic Department of Psychiatry, Barts and The London, Queen Mary's School of Medicine and Dentistry, Whitechapel, London, UK

    D Curtis

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McQuillin, A., Bass, N., Choudhury, K. et al. 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. Mol Psychiatry 14, 614–620 (2009). https://doi.org/10.1038/mp.2008.6

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