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

• Published in: Molecular psychiatry Vol. 14; no. 6; pp. 614 - 620
• Main Authors: McQuillin, A, Bass, N J, Choudhury, K, Puri, V, Kosmin, M, Lawrence, J, Curtis, D, Gurling, H M D
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2009; Nature Publishing Group
• Subjects: Adult and adolescent clinical studies; Affective disorders; Alleles; Amino Acid Substitution - genetics; Arginine - genetics; Behavioral Sciences; Biological and medical sciences; Biological Psychology; Bipolar disorder; Bipolar Disorder - genetics; Case-Control Studies; Cell receptors; Central nervous system; Chromosome 12; Chromosomes; Chromosomes, Human, Pair 12; Depression; Depressive Disorder - genetics; Dimerization; Disease susceptibility; Emotional disorders; Etiology; Gene Frequency; Gene mapping; Gene mutations; Genes; Genes, Dominant; Genetic aspects; Genetic markers; Genetic Predisposition to Disease; Glutamine; Glutamine - genetics; Haplotypes; Health aspects; Health sciences; Heterozygote; Heterozygotes; Homozygote; Homozygotes; Humans; Linkage Disequilibrium; Medical sciences; Medicine; Medicine & Public Health; Mental depression; Mental health; Microsatellite Repeats; Microsatellites; Mood disorders; Neurosciences; original-article; Pharmacotherapy; Physiological aspects; Polymorphism; Protein interaction; Proteins; Psychiatry; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Receptors, Purinergic P2 - genetics; Receptors, Purinergic P2X7; Risk factors; Single-nucleotide polymorphism; University colleges; United Kingdom; United Kingdom > UK; replication; association; mood disorder; haplotype; depression; Mood disorder; Depression; Case control study; Genetic determinism; Protein; Affective disorder; Arginine; Purinergic receptor; Aminoacid; Genetics; Haplotype; Glutamine
• DOI: 10.1038/mp.2008.6
• ISSN: 1359-4184

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.