TY - JOUR
T1 - Two non-synonymous markers in PTPN21, identified by genome-wide association study data-mining and replication, are associated with schizophrenia
AU - The International schizophrenia consortium
AU - Chen, Jingchun
AU - Lee, Grace
AU - Fanous, Ayman H.
AU - Zhao, Zhongming
AU - Jia, Peilin
AU - O'neill, Anthony
AU - Walsh, Dermot
AU - Kendler, Kenneth S.
AU - Chen, Xiangning
AU - O’Donovan, Michael C.
AU - Kirov, George K.
AU - Craddock, Nick J.
AU - Holmans, Peter A.
AU - Williams, Nigel M.
AU - Georgieva, Lyudmila
AU - Nikolov, Ivan
AU - Norton, N.
AU - Williams, H.
AU - Toncheva, Draga
AU - Milanova, Vihra
AU - Owen, Michael J.
AU - Hultman, Christina M.
AU - Lichtenstein, Paul
AU - Thelander, Emma F.
AU - Sullivan, Patrick
AU - Morris, Derek W.
AU - O’Dushlaine, Colm T.
AU - Kenny, Elaine
AU - Quinn, Emma M.
AU - Gill, Michael
AU - Corvin, Aiden
AU - McQuillin, Andrew
AU - Choudhury, Khalid
AU - Datta, Susmita
AU - Pimm, Jonathan
AU - Thirumalai, Srinivasa
AU - Puri, Vinay
AU - Krasucki, Robert
AU - Lawrence, Jacob
AU - Quested, Digby
AU - Bass, Nicholas
AU - Gurling, Hugh
AU - Crombie, Caroline
AU - Fraser, Gillian
AU - Kuan, Soh Leh
AU - Walker, Nicholas
AU - St Clair, David
AU - Blackwood, Douglas H.R.
AU - Muir, Walter J.
AU - McGhee, Kevin A.
N1 - Funding Information:
The authors thank the volunteers, patients and their family members for participating in this study. This study was supported in part by a research grant ( 07R-1770 ) from the Stanley Medical Research Institute and an Independent Investigator Award from NARSAD to XC, and by grants to investigators involved in the collection and analyses of the datasets from CATIE , GAIN , and the International Schizophrenia Consortium (ISC) . The principal investigators of the CATIE trial were Jeffrey A. Lieberman, T. Scott Stroup, and Joseph P. McEvoy. The CATIE trial was funded by a grant from the National Institute of Mental Health ( N01 MH900001 ) along with MH074027 (PI PF Sullivan). Genotyping was funded by Eli Lilly and Company . The principle investigators for the MGS were Pablo Gejman and Douglas Levinson. MGS study was supported by funding from the National Institute of Mental Health and the National Alliance for Research on Schizophrenia and Depression . Genotyping of part of the sample was supported by GAIN and the Paul Michael Donovan Charitable Foundation . Genotyping was carried out by the Center for Genotyping and Analysis at the Broad Institute of Harvard and MIT with support from the National Center for Research Resources .
PY - 2011/9/1
Y1 - 2011/9/1
N2 - 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.
AB - 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.
KW - Data-mining
KW - Genetic association study
KW - Informatic prioritization
KW - Non-synonymous snp
KW - PTPN21
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U2 - 10.1016/j.schres.2011.06.023
DO - 10.1016/j.schres.2011.06.023
M3 - Article
C2 - 21752600
AN - SCOPUS:80051782509
SN - 0920-9964
VL - 131
SP - 43
EP - 51
JO - Schizophrenia Research
JF - Schizophrenia Research
IS - 1-3
ER -