Regulatory Variant rs2535629 in ITIH3 Intron Confers Schizophrenia Risk By Regulating CTCF Binding and SFMBT1 Expression

Abstract

Genome‐wide association studies have identified 3p21.1 as a robust risk locus for schizophrenia. However, the underlying molecular mechanisms remain elusive. Here a functional regulatory variant (rs2535629) is identified that disrupts CTCF binding at 3p21.1. It is confirmed that rs2535629 is also significantly associated with schizophrenia in Chinese population and the regulatory effect of rs2535629 is validated. Expression quantitative trait loci analysis indicates that rs2535629 is associated with the expression of three distal genes (GLT8D1, SFMBT1, and NEK4) in the human brain, and CRISPR‐Cas9‐mediated genome editing confirmed the regulatory effect of rs2535629 on GLT8D1, SFMBT1, and NEK4. Interestingly, differential expression analysis of GLT8D1, SFMBT1, and NEK4 suggested that rs2535629 may confer schizophrenia risk by regulating SFMBT1 expression. It is further demonstrated that Sfmbt1 regulates neurodevelopment and dendritic spine density, two key pathological characteristics of schizophrenia. Transcriptome analysis also support the potential role of Sfmbt1 in schizophrenia pathogenesis. The study identifies rs2535629 as a plausibly causal regulatory variant at the 3p21.1 risk locus and demonstrates the regulatory mechanism and biological effect of this functional variant, indicating that this functional variant confers schizophrenia risk by altering CTCF binding and regulating expression of SFMBT1, a distal gene which plays important roles in neurodevelopment and synaptic morphogenesis.

Characteristics of changes in plasma proteome profiling after sleeve gastrectomy

“…ITIH3 encodes the heavy chain subunit of the pro-α-trypsin inhibitor complex, which plays a role in promoting the stability of the extracellular matrix by covalently bonding with hyaluronic acid ( 57 ). Polymorphisms of ITIH3 have been associated with an increased risk for schizophrenia and major depressive disorder ( 58 , 59 ). ITIH3 has also demonstrated antitumoral and antimetastatic properties, making it a potential biomarker for various types of cancer such as pancreatic cancer, prostate cancer, stomach cancer, and lung adenocarcinoma ( 60 – 62 ).…”

A functional schizophrenia-associated genetic variant near the TSNARE1 and ADGRB1 genes

“… 22 Now, we are able to generate, study, and compare human neuronal cells with only a single nucleotide difference across the entire genome, as we and others have previously reported. 21 , 30 , 67 , 68 , 69 , 70 , 71 This approach provides the opportunity to elucidate the individual contributions of risk variants in a human- and disease-relevant system. Here, we apply this strategy to study a GWAS-identified, non-coding variant implicated in SCZ risk, rs4129585.…”

An updated catalog of CTCF variants associated with neurodevelopmental disorder phenotypes

“…One example shows that genetic variant rs2535629 confers risk of schizophrenia by mutating a CTCF binding site near the promoter of SFMBT1. This mutation impairs CTCF binding, causing deregulated expression of SFMBT1, a gene that plays roles in neurodevelopmental processes and synaptic morphogenesis (Li et al, 2022 ). It has been proposed that neurodevelopmental disorders and psychiatric disorders are exist on a spectrum, which are linked via shared molecular pathways (Morris-Rosendahl and Crocq, 2020 ).…”