CHI3L1 – Schizophrenia

Chitinase-3-like 1 (CHI3L1) encodes YKL-40, a secreted glycoprotein involved in cellular survival and inflammatory signaling in the brain. An initial Chinese case-control study identified significant association of a promoter SNP (rs10399805; p = .018) and an intron 7 SNP (rs2275351; p = .008) with schizophrenia susceptibility (PMID:18281018). The rs10399805 variant lies at c.−247, disrupting a C/EBP-AML-1 binding site in the promoter and is predicted to upregulate CHI3L1 transcription, in agreement with increased postmortem expression in schizophrenia patients.

Replication in a Caucasian sample of 375 cases and 812 controls confirmed association of the same promoter risk allele with schizophrenia (PMID:18281018). A subsequent Japanese multi-center study of 1463 cases and 1795 controls, together with a meta-analysis encompassing 3005 cases, 3825 controls, and 601 trios, demonstrated significant association of rs4950928 in the promoter region (p = 0.009; global haplotype p < 0.001) but revealed ethnic heterogeneity for rs10399805 and rs4950928 (PMID:20051317).

Schizophrenia’s inheritance is multifactorial; no familial segregation analyses have been reported for CHI3L1 variants. Affected relatives count remains zero, consistent with a polygenic risk model rather than Mendelian inheritance. Clinical features influenced by CHI3L1 risk alleles include psychosis and cognitive performance, with carriers of the promoter variant presenting fewer positive symptoms and relatively spared cognition.

Variant spectrum is limited to common regulatory alleles: primarily c.-247C>T (rs10399805) and promoter SNP rs4950928. Both show recurrent risk associations across Asian and European populations but require denser genotyping than standard WGA arrays. Functional in silico and expression data predict that c.-247C>T amplifies CHI3L1 transcription in neural cells.

Functional concordance is supported by postmortem analyses reporting elevated CHI3L1 expression in hippocampus and prefrontal cortex of schizophrenia patients. The promoter c.-247C>T substitution disrupts transcription factor binding (C/EBP-AML-1), aligning mechanistic predictions with observed gene overexpression in disease-relevant tissues.

Although moderate genetic and experimental evidence supports CHI3L1 as a schizophrenia susceptibility gene, ethnic heterogeneity and the absence of Mendelian segregation analyses limit clinical validity. Additional large-scale studies and functional models are needed to refine risk estimates. Key take-home: CHI3L1 promoter variants confer moderate risk for schizophrenia and may serve as biomarkers or therapeutic targets pending further validation.

References

• Biological psychiatry • 2008 • Chitinase-3-like 1 (CHI3L1) gene and schizophrenia: genetic association and a potential functional mechanism. PMID:18281018
• Schizophrenia research • 2010 • The chitinase 3-like 1 gene and schizophrenia: evidence from a multi-center case-control study and meta-analysis. PMID:20051317

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