title: 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.
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.
authors.affiliation: Molecular Psychiatry Laboratory, Department of Mental Health Sciences, Windeyer Institute of Medical Sciences, Royal Free and University College Medical School, University College London, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: McQuillin
authors.forename: N J
authors.initials: NJ
authors.lastname: Bass
authors.forename: K
authors.initials: K
authors.lastname: Choudhury
authors.forename: V
authors.initials: V
authors.lastname: Puri
authors.forename: M
authors.initials: M
authors.lastname: Kosmin
authors.forename: J
authors.initials: J
authors.lastname: Lawrence
authors.forename: D
authors.initials: D
authors.lastname: Curtis
authors.forename: H M D
authors.initials: HM
authors.lastname: Gurling
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics*; D001120:Arginine / Q000235:genetics; D001714:Bipolar Disorder / Q000235:genetics*; D016022:Case-Control Studies; D002881:Chromosomes, Human, Pair 12; D003866:Depressive Disorder / Q000235:genetics*; D005787:Gene Frequency; D005799:Genes, Dominant; D020022:Genetic Predisposition to Disease; D005973:Glutamine / Q000235:genetics; D006239:Haplotypes; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D015810:Linkage Disequilibrium; D018895:Microsatellite Repeats; D018048:Receptors, Purinergic P2 / Q000235:genetics*; D058486:Receptors, Purinergic P2X7
chemical_list: C546468:P2RX7 protein, human; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D005973:Glutamine; D001120:Arginine