TY - JOUR
T1 - Chitinase-3-Like 1 (CHI3L1) Gene and Schizophrenia
T2 - Genetic Association and a Potential Functional Mechanism
AU - Yang, Mao Sheng
AU - Morris, Derek W.
AU - Donohoe, Gary
AU - Kenny, Elaine
AU - O'Dushalaine, Colm T.
AU - Schwaiger, Siobhan
AU - Nangle, Jeanne Marie
AU - Clarke, Sarah
AU - Scully, Paul
AU - Quinn, John
AU - Meagher, David
AU - Baldwin, Patrizia
AU - Crumlish, Niall
AU - O'Callaghan, Eadbhard
AU - Waddington, John L.
AU - Gill, Michael
AU - Corvin, Aiden
PY - 2008/7/15
Y1 - 2008/7/15
N2 - Background: Gene expression data and association analyses in two Chinese samples implicate chitinase 3-like 1 (CHI3L1), a cellular survival gene, in schizophrenia susceptibility. Methods: We tested whether the association data are robust to replication in a Caucasian schizophrenia sample and performed a comprehensive investigation of common genetic variation at the locus. Results: In a sample of 375 case and 812 control subjects we identified significant association with the same risk allele at the promoter single nucleotide polymorphism (SNP) associated in the original study (rs10399805; p = .018) and with another SNP at intron 7 of CHI3L1 (rs2275351; p = .008). The rs10399805 SNP is located at position -247 and disrupts the C/EBP-AML-1 binding site in the gene promoter; the risk allele is predicted to increase CHI3L1 expression, as has been reported in several postmortem schizophrenia studies. Carriers of the risk variant presented with fewer positive symptoms and relatively spared cognitive performance compared with other schizophrenia patients. Conclusions: These findings support a functional mechanism for involvement of CHI3L1 in schizophrenia susceptibility, possibly contributing to a less severe illness. The associated variants in this study are not well tagged by all Whole-Genome Association (WGA) platforms, suggesting additional genotyping may be necessary despite the imminent availability of WGA data from large SZ samples. Because CHI3L1 may be involved in transmission of stress-induced cellular responses, studies of interaction with known environmental risk factors may also be warranted.
AB - Background: Gene expression data and association analyses in two Chinese samples implicate chitinase 3-like 1 (CHI3L1), a cellular survival gene, in schizophrenia susceptibility. Methods: We tested whether the association data are robust to replication in a Caucasian schizophrenia sample and performed a comprehensive investigation of common genetic variation at the locus. Results: In a sample of 375 case and 812 control subjects we identified significant association with the same risk allele at the promoter single nucleotide polymorphism (SNP) associated in the original study (rs10399805; p = .018) and with another SNP at intron 7 of CHI3L1 (rs2275351; p = .008). The rs10399805 SNP is located at position -247 and disrupts the C/EBP-AML-1 binding site in the gene promoter; the risk allele is predicted to increase CHI3L1 expression, as has been reported in several postmortem schizophrenia studies. Carriers of the risk variant presented with fewer positive symptoms and relatively spared cognitive performance compared with other schizophrenia patients. Conclusions: These findings support a functional mechanism for involvement of CHI3L1 in schizophrenia susceptibility, possibly contributing to a less severe illness. The associated variants in this study are not well tagged by all Whole-Genome Association (WGA) platforms, suggesting additional genotyping may be necessary despite the imminent availability of WGA data from large SZ samples. Because CHI3L1 may be involved in transmission of stress-induced cellular responses, studies of interaction with known environmental risk factors may also be warranted.
KW - Binding site
KW - C/EBP-AML-1
KW - CHI3L1 gene
KW - function
KW - genetic association
KW - schizophrenia
UR - http://www.scopus.com/inward/record.url?scp=45449116310&partnerID=8YFLogxK
U2 - 10.1016/j.biopsych.2007.12.012
DO - 10.1016/j.biopsych.2007.12.012
M3 - Article
C2 - 18281018
AN - SCOPUS:45449116310
SN - 0006-3223
VL - 64
SP - 98
EP - 103
JO - Biological Psychiatry
JF - Biological Psychiatry
IS - 2
ER -