Two non-synonymous markers in PTPN21, identified by genome-wide association study data-mining and replication, are associated with schizophrenia

We conducted data-mining analyses of genome wide association (GWA) studies of the CATIE and MGS-GAIN datasets, and found 13 markers in the two physically linked genes, PTPN21 and EML5, showing nominally significant association with schizophrenia. Linkage disequilibrium (LD) analysis indicated that all 7 markers from PTPN21 shared high LD (r2 > 0.8), including rs2274736 and rs2401751, the two non-synonymous markers with the most significant association signals (rs2401751, P = 1.10 × 10− 3 and rs2274736, P = 1.21 × 10− 3). In a meta‐analysis of all 13 replication datasets with a total of 13,940 subjects, we found that the two non-synonymous markers are significantly associated with schizophrenia (rs2274736, OR = 0.92, 95% CI: 0.86–0.97, P = 5.45 × 10− 3 and rs2401751, OR = 0.92, 95% CI: 0.86–0.97, P = 5.29 × 10− 3). One SNP (rs7147796) in EML5 is also significantly associated with the disease (OR = 1.08, 95% CI: 1.02‐1.14, P = 6.43 × 10− 3). These 3 markers remain significant after Bonferroni correction. Furthermore, haplotype conditioned analyses indicated that the association signals observed between rs2274736/rs2401751 and rs7147796 are statistically independent. Given the results that 2 non-synonymous markers in PTPN21 are associated with schizophrenia, further investigation of this locus is warranted.