A functional missense variant in ITIH3 affects protein expression and neurodevelopment and confers schizophrenia risk in the Han Chinese population

Li, Kaiqin; Li, Yifan; Wang, Junyang; Huo, Yongxia; Huang, Di; Li, Shiwu; Liu, Jiewei; Li, Xiaoyan; Liu, Rong; Chen, Xiaogang; Yao, Yong-Gang; Chen, Ceshi; Xiao, Xiao; Li, Ming; Luo, Xiong-Jian

doi:10.1016/j.jgg.2020.04.001

Cited by 11 publications

(21 citation statements)

References 72 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…SCZ cases were from inpatient and outpatient services of collaborating mental health centers of China. Part of cases has been described in our previous studies for candidate gene analyses [ 32 – 34 ]. Diagnosis was based on Diagnostic and Statistical Manual of mental disorders (DSM-IV) criteria, with the use of Structured Clinical Interview for DSM-IV (SCID) Axis I Disorders.…”

Section: Methodsmentioning

confidence: 99%

“…All relevant and detailed information (including onset of SCZ, first onset or remitted, symptoms and chief complaint, duration course, family history of psychiatric disorders, medication history) were carefully evaluated by at least two independent experienced psychiatrists to reach a consensus DSM-IV diagnosis. Detailed information about diagnosis had been described in previous studies [ 33 , 34 ] . The average age of cases and controls were 35.67 ± 10.29 and 28.82 ± 6.83 years, respectively.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Genome-wide association study followed by trans-ancestry meta-analysis identify 17 new risk loci for schizophrenia

Liu

et al. 2021

BMC Med

Self Cite

View full text Add to dashboard Cite

Background Over 200 schizophrenia risk loci have been identified by genome-wide association studies (GWASs). However, the majority of risk loci were identified in populations of European ancestry (EUR), potentially missing important biological insights. It is important to perform 5 GWASs in non-European populations. Methods To identify novel schizophrenia risk loci, we conducted a GWAS in Han Chinese population (3493 cases and 4709 controls). We then performed a large-scale meta-analysis (a total of 143,438 subjects) through combining our results with previous GWASs conducted in EAS and EUR. In addition, we also carried out comprehensive post-GWAS analysis, including heritability partitioning, enrichment of schizophrenia associations in tissues and cell types, trancscriptome-wide association study (TWAS), expression quantitative trait loci (eQTL) and differential expression analysis. Results We identified two new schizophrenia risk loci, including associations in SHISA9 (rs7192086, P = 4.92 × 10-08) and PES1 (rs57016637, P = 2.33 × 10−11) in Han Chinese population. A fixed-effect meta-analysis (a total of 143,438 subjects) with summary statistics from EAS and EUR identifies 15 novel genome-wide significant risk loci. Heritability partitioning with linkage disequilibrium score regression (LDSC) reveals a significant enrichment of schizophrenia heritability in conserved genomic regions, promoters, and enhancers. Tissue and cell-type enrichment analyses show that schizophrenia associations are significantly enriched in human brain tissues and several types of neurons, including cerebellum neurons, telencephalon inhibitory, and excitatory neurons. Polygenic risk score profiling reveals that GWAS summary statistics from trans-ancestry meta-analysis (EAS + EUR) improves prediction performance in predicting the case/control status of our sample. Finally, transcriptome-wide association study (TWAS) identifies risk genes whose cis-regulated expression change may have a role in schizophrenia. Conclusions Our study identifies 17 novel schizophrenia risk loci and highlights the importance and necessity of conducting genetic study in different populations. These findings not only provide new insights into genetic etiology of schizophrenia, but also facilitate to delineate the pathophysiology of schizophrenia and develop new therapeutic targets.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Genome-wide association study followed by trans-ancestry meta-analysis identify 17 new risk loci for schizophrenia

Liu

et al. 2021

BMC Med

Self Cite

View full text Add to dashboard Cite

show abstract

“…We isolated mNSCs according to the published protocols 36 , 37 with some minor modifications as described in our recent study. 38 In brief, brains of mouse embryos (embryonic day 13.5 (E13.5), C57BL/6) were dissected under microscope to obtain neural stem cells from the ventricular zone (VZ) and sub-ventricular zone (SVZ) tissues. Details about isolation and culturing of mNSCs are provided in supplementary material .…”

Section: Methodsmentioning

confidence: 99%

“…Proliferation assays (including EdU incorporation and CCK-8) were performed as previously described 38 and detailed procedures were provided in supplementary methods .…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Integrative Analyses Followed by Functional Characterization Reveal TMEM180 as a Schizophrenia Risk Gene

Wang

et al. 2021

Schizophrenia Bulletin

Self Cite

View full text Add to dashboard Cite

Recent large-scale integrative analyses (including Transcriptome-Wide Association Study [TWAS] and Summary-data-based Mendelian Randomization [SMR]) have identified multiple genes whose cis-regulated expression changes may confer risk of schizophrenia. Nevertheless, expression quantitative trait loci (eQTL) data and genome-wide associations used for integrative analyses were mainly from populations of European ancestry, resulting in potential missing of pivotal biological insights in other continental populations due to population heterogeneity. Here we conducted TWAS and SMR integrative analyses using blood eQTL (from 162 subjects) and GWAS data (22 778 cases and 35 362 controls) of schizophrenia in East Asian (EAS) populations. Both TWAS (P = 2.89 × 10–14) and SMR (P = 6.04 × 10–5) analyses showed that decreased TMEM180 mRNA expression was significantly associated with risk of schizophrenia. We further found that TMEM180 was significantly down-regulated in the peripheral blood of schizophrenia cases compared with controls (P = 8.63 × 10–4 in EAS sample), and its expression was also significantly lower in the brain tissues of schizophrenia cases compared with controls (P = 1.87 × 10–5 in European sample from PsychENCODE). Functional explorations suggested that Tmem180 knockdown affected neurodevelopment, ie, proliferation and differentiation of neural stem cells. RNA sequencing showed that pathways regulated by Tmem180 were significantly enriched in brain development and synaptic transmission. In conclusion, our study provides convergent lines of evidence for the involvement of TMEM180 in schizophrenia, and highlights the potential and importance of resource integration and sharing at this big data era in bio-medical research.

show abstract

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

et al. 2022

Advanced Science

Self Cite

View full text Add to dashboard Cite

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.

show abstract

A functional missense variant in ITIH3 affects protein expression and neurodevelopment and confers schizophrenia risk in the Han Chinese population

Cited by 11 publications

References 72 publications

Genome-wide association study followed by trans-ancestry meta-analysis identify 17 new risk loci for schizophrenia

Genome-wide association study followed by trans-ancestry meta-analysis identify 17 new risk loci for schizophrenia

Integrative Analyses Followed by Functional Characterization Reveal TMEM180 as a Schizophrenia Risk Gene

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

Contact Info

Product

Resources

About