Abstract
Recently, two genome-wide association studies (GWASs) of schizophrenia (SCZ) in Han Chinese identified several susceptibility loci. Replication efforts aiming to validate the GWAS findings were made and focused on the top hits. We conducted a more extensive follow-up study in an independent sample of 1471 cases and 1528 matched controls to verify 26 genetic variants by including nine top single-nucleotide polymorphisms (SNPs) that reached genome-wide significance and 17 promising SNPs nominated in the initial discovery phase. rs8073471 in an intron of tubulin-folding cofactor D (TBCD) obtained nominal significance (P<0.01) in single SNP analysis. Logistic regression identified significant interaction between rs3744165 (5’-untranslated region variant of exon 2 of zinc finger protein 750 (ZNF750), and in an intron of TBCD) and rs8073471 (Deviance test P-value=2.77 × 10−34). Both SNPs are located at 17q25, an interesting region that has been implicated in SCZ. By using the Genotype-Tissue Expression (GTEx) data set, we implemented an expression quantitative trait loci epistasis analysis to explore the association between the genotype combinations of the two SNPs and gene expression levels in 13 areas of human central nervous system. We observed that rs3744165 × rs8073471 interaction modulated the expression profile of TEAD3 (P=1.87 × 10−8), SH3TC2 (P=2.00 × 10−8), KCNK9 (P=5.20 × 10−7) and PPDPF (P=1.13 × 10−6) in postmortem cortex tissue; EFNA1 (P=7.26 × 10−9), RNU4ATAC (P=2.32 × 10−8) and NUPL2 (P=6.79 × 10−8) in cerebellum tissue. To the best of our knowledge, our study is the first one that links TBCD and ZNF750 mutations to SCZ susceptibility and to the transcript levels in human brain tissues. Further efforts are needed to understand the role of those variants in the pathogenesis of SCZ.
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Acknowledgements
The authors gratefully acknowledge the support from the National Basic Research Program of China (2014CB744600), and National Nature Science Foundation of China (81201039). We highly appreciated the solid supports from Professor Xin Yu and Professor Rene Kahn on organizing the GREAT-CN network. The GTEx Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health (commonfund.nih.gov/GTEx). Additional funds were provided by the NCI, NHGRI, NHLBI, NIDA, HIMH and NINDS. Donors were enrolled at Biospecimen Source Sites funded by NCI\Leidos Biomedical Research subcontracts to the National Disease Research Interchange (10XS170), Roswell Park Cancer Institute (10XS171), and Science Care (X10S172). The Laboratory, Data Analysis and Coordinating Center (LDACC) were funded through a contract (HHSN268201000029C) to The Broad Institute. Biorepository operations were funded through a Leidos Biomedical Research subcontract to Van Andel Research Institute (10ST1035). Additional Data repository and project management were provided by Leidos Biomedical Research (HHSN261200800001E). The Brain Bank was supported supplements to University of Miami grant DA006227. Statistical Methods development grants were made to the University of Geneva (MH090941 and MH101814), the University of Chicago (MH090951, MH090937, MH101825 and MH101820), the University of North Carolina—Chapel Hill (MH090936), North Carolina State University (MH101819), Harvard University (MH090948), Stanford University (MH101782), Washington University (MH101810) and to the University of Pennsylvania (MH101822). The data sets used for the analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000424.v4.p1.
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Guan, L., Wang, Q., Wang, L. et al. Common variants on 17q25 and gene–gene interactions conferring risk of schizophrenia in Han Chinese population and regulating gene expressions in human brain. Mol Psychiatry 21, 1244–1250 (2016). https://doi.org/10.1038/mp.2015.204
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DOI: https://doi.org/10.1038/mp.2015.204
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