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

ABSTRACT: 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.

SUBMITTER: Wang JY

PROVIDER: S-EPMC8379544 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Schizophrenia is a common mental disorder with high heritability and strong genetic heterogeneity. Common disease-common variants hypothesis predicts that schizophrenia is attributable in part to common genetic variants. However, recent studies have clearly demonstrated that copy number variations (CNVs) also play pivotal roles in schizophrenia susceptibility and explain a proportion of missing heritability. Though numerous CNVs have been identified, many of the regions affected by CNVs show poor overlapping among different studies, and it is not known whether the genes disrupted by CNVs contribute to the risk of schizophrenia. By using cumulative scoring, we systematically prioritized the genes affected by CNVs in schizophrenia. We identified 8 top genes that are frequently disrupted by CNVs, including NRXN1, CHRNA7, BCL9, CYFIP1, GJA8, NDE1, SNAP29, and GJA5. Integration of genes affected by CNVs with known schizophrenia susceptibility genes (from previous genetic linkage and association studies) reveals that many genes disrupted by CNVs are also associated with schizophrenia. Further protein-protein interaction (PPI) analysis indicates that protein products of genes affected by CNVs frequently interact with known schizophrenia-associated proteins. Finally, systematic integration of CNVs prioritization data with genetic association and PPI data identifies key schizophrenia candidate genes. Our results provide a global overview of genes impacted by CNVs in schizophrenia and reveal a densely interconnected molecular network of de novo CNVs in schizophrenia. Though the prioritized top genes represent promising schizophrenia risk genes, further work with different prioritization methods and independent samples is needed to confirm these findings. Nevertheless, the identified key candidate genes may have important roles in the pathogenesis of schizophrenia, and further functional characterization of these genes may provide pivotal targets for future therapeutics and diagnostics.

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

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