Phenome-wide association study of P2RX7 identifies schizophrenia and mood disorders as primary associated phenotypes

Objectives P2RX7 has been implicated in bipolar disorder, major depressive disorder, schizophrenia, anxiety disorders, Alzheimer's disease, and Parkinson's disease. However, the specificity and comparability of these associations remain unclear. This study aimed to systematically evaluate multiple neuropsychiatric disorders to identify those most robustly associated with P2RX7 . Methods We analyzed 1861 imputed SNPs spanning the P2RX7 gene in 1,087,925 individuals from 72 independent cohorts across 18 neuropsychiatric disorders. SNP-disease associations were assessed within each cohort, followed by meta-analysis and false discovery rate (FDR) correction to identify significant disease-risk variants. P2RX7 mRNA and protein expression across tissues or cells was characterized. Functional analyses evaluated the regulatory effects of disease-associated SNPs on P2RX7 mRNA expression, subcortical gray matter volumes (GMVs), cortical surface area (SA), and cortical thickness (TH). Results Bipolar disorder showed the strongest association with P2RX7 variants in European Americans (EAs) (4.0 × 10 −8 ≤ p ≤ 0.004; 3.8 × 10 −5 ≤ q ≤ 0.05), followed by schizophrenia in EAs (8.9 × 10 −6 ≤ p ≤ 2.6 × 10 −4 ; 9.4 × 10 −3 ≤ q ≤ 0.043) and Chinese populations (2.1 × 10 −5 ≤ p ≤ 1.7 × 10 −3 ; 6.8 × 10 −3 ≤ q ≤ 0.049), and major depression in both EAs ( p = 4.1 × 10 −5 ; q = 0.030) and Chinese (4.3 × 10 −5 ≤ p ≤ 0.009; 6.1 × 10 −3 ≤ q ≤ 0.046). The significance of most associations and their relative ranking across disorders was maintained in the trans-ancestry meta-analysis. Expression analysis revealed that P2RX7 mRNA and protein expression were abundant in the brain, glial cells and macrophages. Approximately half of the disease-associated SNPs significantly influenced P2RX7 mRNA expression in nine brain regions (1.0 × 10 −7 ≤ p ≤ 0.047) and altered GMV, SA, and TH of seven brain regions (1.9 × 10 −4 ≤ p ≤ 3.4 × 10 −3 ). Conclusion P2RX7 is most consistently and specifically associated with bipolar disorder, schizophrenia, and major depression, supported by both statistical and biological evidence.