title: Common variants on 17q25 and gene-gene interactions conferring risk of schizophrenia in Han Chinese population and regulating gene expressions in human brain.
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.
authors.affiliation: Peking University Sixth Hospital, Peking University Institute of Mental Health, Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China.
authors.forename: L
authors.initials: L
authors.lastname: Guan
authors.affiliation: Department of Statistics, Purdue University, West Lafayette, IN, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Statistics, Purdue University, West Lafayette, IN, USA.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: Peking University Sixth Hospital, Peking University Institute of Mental Health, Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China.
authors.forename: B
authors.initials: B
authors.lastname: Wu
authors.affiliation: Xi'an Mental Health Center, Xi'an, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Xi'an Mental Health Center, Xi'an, China.
authors.forename: F
authors.initials: F
authors.lastname: Liu
authors.affiliation: Shanxi Provincial Mental Health Center, Taiyuan, China.
authors.forename: F
authors.initials: F
authors.lastname: Ye
authors.affiliation: Shanxi Provincial Mental Health Center, Taiyuan, China.
authors.forename: T
authors.initials: T
authors.lastname: Zhang
authors.affiliation: The Mental Health Center of Hebei Province, Baoding, China.
authors.forename: K
authors.initials: K
authors.lastname: Li
authors.affiliation: The Mental Health Center of Hebei Province, Baoding, China.
authors.forename: B
authors.initials: B
authors.lastname: Yan
authors.affiliation: Shandong Mental Health Center, Jinan, China.
authors.forename: C
authors.initials: C
authors.lastname: Lu
authors.affiliation: Shandong Mental Health Center, Jinan, China.
authors.forename: L
authors.initials: L
authors.lastname: Su
authors.affiliation: Mudanjiang Neuro-Psychiatric Hospital of Heilongjiang Province, Mudanjiang, China.
authors.forename: G
authors.initials: G
authors.lastname: Jin
authors.affiliation: Mudanjiang Neuro-Psychiatric Hospital of Heilongjiang Province, Mudanjiang, China.
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.affiliation: Tianjin Anding Hospital, Tianjin, China.
authors.forename: H
authors.initials: H
authors.lastname: Tian
authors.affiliation: Tianjin Anding Hospital, Tianjin, China.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: Hangzhou Seventh People's Hospital, Hangzhou, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Hangzhou Seventh People's Hospital, Hangzhou, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Chongqing Mental Health Center, Chongqing, China.
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.affiliation: Chongqing Mental Health Center, Chongqing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Neuro-Psychiatric Hospital of Fuzhou, Fujian Province, Fuzhou, China.
authors.forename: W
authors.initials: W
authors.lastname: Cong
authors.affiliation: Neuro-Psychiatric Hospital of Fuzhou, Fujian Province, Fuzhou, China.
authors.forename: J
authors.initials: J
authors.lastname: Zheng
authors.affiliation: The First Affiliated Hospital of Kunming Medical University, Kunming, China.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.affiliation: The First Affiliated Hospital of Kunming Medical University, Kunming, China.
authors.forename: X
authors.initials: X
authors.lastname: Xu
authors.affiliation: Renmin Hospital of Wuhan University, Wuhan, China.
authors.forename: H
authors.initials: H
authors.lastname: Liu
authors.affiliation: Renmin Hospital of Wuhan University, Wuhan, China.
authors.forename: W
authors.initials: W
authors.lastname: Xiao
authors.affiliation: Xicheng Ping'an Hospital, Beijing, China.
authors.forename: C
authors.initials: C
authors.lastname: Han
authors.affiliation: Xicheng Ping'an Hospital, Beijing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Institute of Guangdong Province, Guangzhou, China.
authors.forename: F
authors.initials: F
authors.lastname: Jia
authors.affiliation: Institute of Guangdong Province, Guangzhou, China.
authors.forename: X
authors.initials: X
authors.lastname: Qiao
authors.affiliation: Department of Statistics, Purdue University, West Lafayette, IN, USA.
authors.forename: D
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Peking University Sixth Hospital, Peking University Institute of Mental Health, Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China.|Department of Statistics, Purdue University, West Lafayette, IN, USA.
authors.forename: M
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Peking University Sixth Hospital, Peking University Institute of Mental Health, Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China.
authors.forename: H
authors.initials: H
authors.lastname: Ma
mesh_terms: D000328:Adult; D044466:Asian People / Q000235:genetics; D001921:Brain / Q000378:metabolism; D002681:China; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D005006:Ethnicity / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D015870:Gene Expression; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D016015:Logistic Models; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D012559:Schizophrenia / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins
chemical_list: D008869:Microtubule-Associated Proteins; C418662:TBCD protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C570799:ZNF750 protein, human