238. Transcriptome-Wide Isoform-Level Dysregulation in Schizophrenia, Autism, and Bipolar Disorder

Gandal, Michael J.; Pinto, Dalila; Iakoucheva, Lilia M.; Liu, Chunyu; Geschwind, Dan

doi:10.1016/j.biopsych.2019.03.252

Cited by 84 publications

(182 citation statements)

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“…We further explored TMEM180 mRNA expression in brains of schizophrenia cases and controls using expression data from the PsychENCODE. 41 Again, TMEM180 was significantly down-regulated in the brains of schizophrenia cases compared with controls ( P = 1.87 × 10 –5 ), with an effect size (Cohen’s d ) of 0.906. These consistent results from different samples and tissues suggested that dysregulation of TMEM180 might play a role in schizophrenia.…”

Section: Resultsmentioning

confidence: 93%

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

Wang

et al. 2021

Schizophrenia Bulletin

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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.

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Section: Resultsmentioning

confidence: 93%

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

Wang

et al. 2021

Schizophrenia Bulletin

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“…One of the largest studies of transcriptomic brain pathology in schizophrenia was conducted by the PsychENCODE consortium [45]. In this study, gene-and transcript isoform-level differential expression was comprehensively analyzed by performing RNAsequencing (RNA-seq) of bulk postmortem cerebral cortex tissues from 559 schizophrenia cases and 936 control individuals, together with 51 ASD and 222 bipolar disorder brains.…”

Section: Transcriptomic and Epigenomic Pathology In Schizophreniamentioning

confidence: 99%

“…Second, while it must be recognized that collecting human postmortem brains on a large scale requires a great endeavor, there is an open question of whether the sample sizes in studies to date are sufficient. Evaluating the inter-study reproducibility, which may help answer this question, it is true that the result of the analysis of genes differentially expressed between schizophrenia cases and controls in the aforementioned PsychEncode study [45] is well correlated with that of a preceding study by the CommonMind Consortium (CMC) [122] (correlation coefficient between the two studies for 687 genes with FDR < 0.05 in the CMC study = 0.799). On the other hand, of the 23 genes that showed statistical significance after Bonferroni correction in the CMC study (uncorrected P < 3.04 × 10 −6 , 0.05 divided by the number of genes analyzed, 16,423), only nine genes surpassed the same significance threshold in the PsychENCODE study.…”

Section: Current Achievements Limitations and New Directions For Futu...mentioning

confidence: 99%

The molecular pathology of schizophrenia: an overview of existing knowledge and new directions for future research

Nakamura

Takata

2023

Mol Psychiatry

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Despite enormous efforts employing various approaches, the molecular pathology in the schizophrenia brain remains elusive. On the other hand, the knowledge of the association between the disease risk and changes in the DNA sequences, in other words, our understanding of the genetic pathology of schizophrenia, has dramatically improved over the past two decades. As the consequence, now we can explain more than 20% of the liability to schizophrenia by considering all analyzable common genetic variants including those with weak or no statistically significant association. Also, a large-scale exome sequencing study identified single genes whose rare mutations substantially increase the risk for schizophrenia, of which six genes (SETD1A, CUL1, XPO7, GRIA3, GRIN2A, and RB1CC1) showed odds ratios larger than ten. Based on these findings together with the preceding discovery of copy number variants (CNVs) with similarly large effect sizes, multiple disease models with high etiological validity have been generated and analyzed. Studies of the brains of these models, as well as transcriptomic and epigenomic analyses of patient postmortem tissues, have provided new insights into the molecular pathology of schizophrenia. In this review, we overview the current knowledge acquired from these studies, their limitations, and directions for future research that may redefine schizophrenia based on biological alterations in the responsible organ rather than operationalized criteria.

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“…Previously harmonized genotype array and frontal cortex RNA-seq data from PsychEN-CODE [19,74] consisted of uniformly processed data from six studies: BipSeq, LIBD_ szControl, CMC_HBCC, CommonMind, BrainGVEX, and UCLA-ASD. We imputed C4 alleles in six studies from PsychENCODE separately in the same manner as the ABCD dataset using Beagle4.1 with the latest multi-ancestry C4 imputation reference panel.…”

Section: Validation Of Expression Weights For C4 Genes In Psychencodementioning

confidence: 99%

“…org/ 10. 7303/ syn12 080241) [74]. The codes used to perform statistical analyses are available under the MIT license on GitHub (https:// github.…”

Section: Supplementary Informationmentioning

confidence: 99%

Multi-ancestry phenome-wide association of complement component 4 variation with psychiatric and brain phenotypes in youth

et al. 2023

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Background Increased expression of the complement component 4A (C4A) gene is associated with a greater lifetime risk of schizophrenia. In the brain, C4A is involved in synaptic pruning; yet, it remains unclear the extent to which upregulation of C4A alters brain development or is associated with the risk for psychotic symptoms in childhood. Here, we perform a multi-ancestry phenome-wide association study in 7789 children aged 9–12 years to examine the relationship between genetically regulated expression (GREx) of C4A, childhood brain structure, cognition, and psychiatric symptoms. Results While C4A GREx is not related to childhood psychotic experiences, cognition, or global measures of brain structure, it is associated with a localized reduction in regional surface area (SA) of the entorhinal cortex. Furthermore, we show that reduced entorhinal cortex SA at 9–10 years predicts a greater number and severity of psychosis-like events at 1-year and 2-year follow-up time points. We also demonstrate that the effects of C4A on the entorhinal cortex are independent of genome-wide polygenic risk for schizophrenia. Conclusions Our results suggest neurodevelopmental effects of C4A on childhood medial temporal lobe structure, which may serve as a biomarker for schizophrenia risk prior to symptom onset.

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238. Transcriptome-Wide Isoform-Level Dysregulation in Schizophrenia, Autism, and Bipolar Disorder

Cited by 84 publications

References 0 publications

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

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

The molecular pathology of schizophrenia: an overview of existing knowledge and new directions for future research

Multi-ancestry phenome-wide association of complement component 4 variation with psychiatric and brain phenotypes in youth

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