title: Functional variants in the promoter region of Chitinase 3-like 1 (CHI3L1) and susceptibility to schizophrenia.
abstract: The chitinase 3-like 1 gene (CHI3L1) is abnormally expressed in the hippocampus of subjects with schizophrenia and may be involved in the cellular response to various environmental events that are reported to increase the risk of schizophrenia. Here, we provide evidence that the functional variants at the CHI3L1 locus influence the genetic risk of schizophrenia. First, using case-control and transmission/disequilibrium-test (TDT) methodologies, we detected a significant association between schizophrenia and haplotypes within the promoter region of CHI3L1 in two independent cohorts of Chinese individuals. Second, the at-risk CCC haplotype (P=.00058 and .0018 in case-control and TDT studies, respectively) revealed lower transcriptional activity (P=2.2 x 10(-7)) and was associated with lower expression (P=3.1 x 10(-5)) compared with neutral and protective haplotypes. Third, we found that an allele of SNP4 (rs4950928), the tagging SNP of CCC, impaired the MYC/MAX-regulated transcriptional activation of CHI3L1 by altering the transcriptional-factor consensus sequences, and this may be responsible for the decreased expression of the CCC haplotype. In contrast, the protective TTG haplotype was associated with a high level of CHI3L1 expression. Our findings identify CHI3L1 as a potential schizophrenia-susceptibility gene and suggest that the genes involved in the biological response to adverse environmental conditions are likely to play roles in the predisposition to schizophrenia.
authors.affiliation: Bio-X Center, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Xinzhi
authors.initials: X
authors.lastname: Zhao
authors.forename: Ruqi
authors.initials: R
authors.lastname: Tang
authors.forename: Bo
authors.initials: B
authors.lastname: Gao
authors.forename: Yongyong
authors.initials: Y
authors.lastname: Shi
authors.forename: Jian
authors.initials: J
authors.lastname: Zhou
authors.forename: Shengzhen
authors.initials: S
authors.lastname: Guo
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Yabing
authors.initials: Y
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Tang
authors.forename: Junwei
authors.initials: J
authors.lastname: Meng
authors.forename: Sheng
authors.initials: S
authors.lastname: Li
authors.forename: Hongsheng
authors.initials: H
authors.lastname: Wang
authors.forename: Gang
authors.initials: G
authors.lastname: Ma
authors.forename: Chuwen
authors.initials: C
authors.lastname: Lin
authors.forename: Yue
authors.initials: Y
authors.lastname: Xiao
authors.forename: Guoyin
authors.initials: G
authors.lastname: Feng
authors.forename: Zhiguang
authors.initials: Z
authors.lastname: Lin
authors.forename: Shaomin
authors.initials: S
authors.lastname: Zhu
authors.forename: Yangling
authors.initials: Y
authors.lastname: Xing
authors.forename: Hong
authors.initials: H
authors.lastname: Sang
authors.forename: David
authors.initials: D
authors.lastname: St Clair
authors.forename: Lin
authors.initials: L
authors.lastname: He
mesh_terms: D054392:Adipokines; D000328:Adult; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000502:physiology; D016022:Case-Control Studies; D002460:Cell Line; D002681:China; D000071451:Chitinase-3-Like Protein 1; D005260:Female; D016259:Genes, myc / Q000502:physiology; D020022:Genetic Predisposition to Disease; D006023:Glycoproteins / Q000235:genetics* / Q000378:metabolism; D006239:Haplotypes; D006801:Humans; D037102:Lectins; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012559:Schizophrenia / Q000235:genetics*; D015398:Signal Transduction; D015533:Transcriptional Activation
chemical_list: D054392:Adipokines; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C084533:CHI3L1 protein, human; D000071451:Chitinase-3-Like Protein 1; D006023:Glycoproteins; D037102:Lectins; C499330:MAX protein, human