Functional variants in the promoter region of Chitinase 3-like 1 (CHI3L1) and susceptibility to schizophrenia.
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.
Zhao
Xinzhi
X
Bio-X Center, Shanghai Jiao Tong University, Shanghai, China.
Tang
Ruqi
R
Gao
Bo
B
Shi
Yongyong
Y
Zhou
Jian
J
Guo
Shengzhen
S
Zhang
Jing
J
Wang
Yabing
Y
Tang
Wei
W
Meng
Junwei
J
Li
Sheng
S
Wang
Hongsheng
H
Ma
Gang
G
Lin
Chuwen
C
Xiao
Yue
Y
Feng
Guoyin
G
Lin
Zhiguang
Z
Zhu
Shaomin
S
Xing
Yangling
Y
Sang
Hong
H
St Clair
David
D
He
Lin
L
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
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