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

Chen, J., Lee, G., Fanous, A.H., Zhao, Z., Jia, P., O'neill, A., Walsh, D., Kendler, K.S., Chen, X., O'Donovan, M.C. ORCID:, Kirov, G.K. ORCID:, Craddock, N.J. ORCID:, Holmans, P.A. ORCID:, Williams, N.M. ORCID:, Georgieva, L., Nikolov, I., Norton, N., Williams, H. J. ORCID:, Toncheva, D., Milanova, V., Owen, M.J. ORCID:, Hultman, C.M., Lichtenstein, P., Thelander, E.F., Sullivan, P., Morris, D.W., O'Dushlaine, C.T., Kenny, E., Quinn, E.M., Gill, M., Corvin, A., McQuillin, A., Choudhury, K., Datta, S., Pimm, J., Thirumalai, S., Puri, V., Krasucki, R., Lawrence, J., Quested, D., Bass, N., Gurling, H., Crombie, C., Fraser, G., Kuan, S.L., Walker, N., St Clair, D., Blackwood, D.H.R., Muir, W.J., McGhee, K.A., Pickard, B., Malloy, P., Maclean, A.W., Van Beck, M., Wray, N.R., Macgregor, S., Visscher, P.M., Pato, M.T., Medeiros, H., Middleton, F., Carvalho, C., Morley, C., Fanous, A., Conti, D., Knowles, J.A., Paz Ferreira, C., Macedo, A., Helena Azevedo, M., Pato, C.N., Stone, J.L., Ruderfer, D.M., Kirby, A.N., Ferreira, M.A.R., Daly, M.J., Purcell, S.M., Sklar, P., Stone, J.L., Chambert, K., Kuruvilla, F., Gabriel, S.B., Ardlie, K., Moran, J.L. and Scolnick, E.M. 2011. Two non-synonymous markers in PTPN21, identified by genome-wide association study data-mining and replication, are associated with schizophrenia. Schizophrenia Research 131 (1-3) , pp. 43-51. 10.1016/j.schres.2011.06.023

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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.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Medicine
Date of Acceptance: 20 June 2011
Last Modified: 25 Nov 2022 12:17

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