Pairwise common variant meta-analyses of schizophrenia with other psychiatric disorders reveals shared and distinct gene and gene-set associations

Cairns, Murray J.

doi:10.1101/725614

Cited by 12 publications

(16 citation statements)

References 49 publications

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“…Its significant transcript was ENST00000463042, p =5.80E-11, in which the higher expression had a protective effect on the risk of schizophrenia (causal effect beta= 0.135±0.021). Consistently, William and Murray found predicted expression of SDCCAG8 was associated with higher risk of schizophrenia in the DLPFC 32 . Similar to the estimation based on the gene-level expression, many genes with fewer and even no hit papers might be also promising causal genes (Excel Table S4).…”

Section: Resultsmentioning

confidence: 60%

Systematic comparative analysis of Mendelian randomization methods for inferring causal genes of complex phenotypes and the application to psychiatric diseases

Jiang¹,

et al. 2020

Preprint

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Isolating causal genes from enormous genome-wide association signals of complex phenotypes remains an open and challenging question. SMR (Summary-based Mendelian Randomization) is a widely used Mendelian randomization (MR) method for inferring causal genes by using a single expression quantitative trait locus (eQTL). In the present study, we explored more powerful MR methods based on multiple eQTLs. Among six representative multiple instrumental variable (IVs) based MR methods, original used in the epidemiological field, not all MR methods worked for the causal gene estimation. But we found the maximum-likelihood based MR method and weighted median-based MR method were preferable to the other four MR methods in terms of valid type 1 errors, acceptable statistical powers and robustness to linkage disequilibrium (LD) in eQTLs. Both of the MR methods were also much more powerful than the SMR. We recalibrated key parameters of the two MR methods in practices and developed a multiple IVs based MR analysis framework for causal gene estimation, named MACG and available at http://pmglab.top/kggsee. In the applications, MACG not only rediscovered many known causal genes of the schizophrenia and bipolar disorder, but also reported plenty of promising candidate causal genes. In conclusion, this study provided a powerful tool and encouraging exemplars of mining potential causal genes from huge amounts of GWAS signals with eQTLs.

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Section: Resultsmentioning

confidence: 60%

Systematic comparative analysis of Mendelian randomization methods for inferring causal genes of complex phenotypes and the application to psychiatric diseases

Jiang¹,

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

Section: Methodsmentioning

confidence: 99%

“…An extension of 5 kilobases (kb) upstream of the gene, and 1.5 kb downstream was the conservative construct, whilst a larger 35 kb upstream and 10 kb downstream was the liberal construct. Boundaries were longer upstream of the gene in both instances to capture more promoter related variation, as is usual practice [53][54][55] Genic P-values were transformed to Z-scores with the probit function for input into the geneset association model. Competitive gene-set association was undertaken by a linear regression model whereby genic Z-scores are the outcome and confounders including gene size and genic minor allele count included as covariates.…”

Section: Generation Pharmagenic Enrichment Score (Pes) Candidate Gene-setsmentioning

confidence: 99%

Genetically informed precision drug repurposing for lung function and implications for respiratory infection

Shair

Geaghan

Riveros

et al. 2020

Preprint

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Impaired lung function is associated with significant morbidity and mortality. Restrictive and obstructive lung disorders are a large contributor to decreased lung function, as well as the acute impact of infection. Measures of pulmonary function are heritable, and thus, we sought to utilise genomics to propose novel drug repurposing candidates which could improve respiratory outcomes. Lung function measures were found to be genetically correlated with metabolic and hormone traits which could be pharmacologically modulated, with a causal effect of increased fasting glucose on diminished lung function supported by latent causal variable models and Mendelian randomisation. We developed polygenic scores for lung function specifically within pathways with known drug targets to prioritise individuals who may benefit from particular drug repurposing opportunities, accompanied by transcriptome-wide association studies to identify drug-gene interactions with potential lung function increasing modes of action. These drug repurposing candidates were further considered relative to the host-viral interactome of three viruses with associated respiratory pathology (SARS-CoV2, influenza, and human adenovirus). We uncovered an enrichment amongst glycaemic pathways of human proteins which putatively interact with virally expressed SARS-CoV2 proteins, suggesting that antihyperglycaemic agents may have a positive effect both on lung function and SARS-CoV2 progression.

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“…The heterozygous mutations in Ash1l , previously identified by whole exome sequencing (WES), are strongly enriched for variants likely to increase nervous system disease risk (Faundes et al., 2018), including TS, ASD, ADHD, multiple congenital malformation (MCA)/intellectual disability (ID), and SCZ (Cravedi et al., 2017; Kern et al., 2015; Liu et al., 2020; Okamoto et al., 2017; Penzes et al., 2013; Reay & Cairns, 2020; Satterstrom et al., 2019; Toro et al., 2010; Wang et al., 2016). Ash1l is a methyltransferase that catalyzes H3K36me2 at specific locations on the histone tail and plays a critical role in maintaining active gene expression (Gregory et al., 2007).…”

Section: Mutations In Ash1l Confer Susceptibility To Tourette Syndromementioning

confidence: 99%

Role of Ash1l in Tourette syndrome and other neurodevelopmental disorders

Zhang

Zheng

et al. 2020

Developmental Neurobiology

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Ash1l potentially contributes to neurodevelopmental diseases. Although specific Ash1l mutations are rare, they have led to informative studies in animal models that may bring therapeutic advances. Ash1l is highly expressed in the brain and correlates with the neuropathology of Tourette syndrome (TS), autism spectrum disorder, and intellectual disability during development, implicating shared epigenetic factors and overlapping neuropathological mechanisms. Functional convergence of Ash1l generated several significant signaling pathways: chromatin remodeling and transcriptional regulation, protein synthesis and cellular metabolism, and synapse development and function. Here, we systematically review the literature on Ash1l, including its discovery, expression, function, regulation, implication in the nervous system, signaling pathway, mutations, and putative involvement in TS and other neurodevelopmental traits. Such findings highlight Ash1l pleiotropy and the necessity of transcending a single gene to complicated mechanisms of network convergence underlying these diseases. With the progress in functional genomic analysis (highlighted in this review), and although the importance and necessity of Ash1l becomes increasingly apparent in the medical field, further research is required to discover the precise function and molecular regulatory mechanisms related to Ash1l. Thus, a new perspective is proposed for basic scientific research and clinical interventions for cross‐disorder diseases.

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Pairwise common variant meta-analyses of schizophrenia with other psychiatric disorders reveals shared and distinct gene and gene-set associations

Cited by 12 publications

References 49 publications

Systematic comparative analysis of Mendelian randomization methods for inferring causal genes of complex phenotypes and the application to psychiatric diseases

Systematic comparative analysis of Mendelian randomization methods for inferring causal genes of complex phenotypes and the application to psychiatric diseases

Genetically informed precision drug repurposing for lung function and implications for respiratory infection

Role of Ash1l in Tourette syndrome and other neurodevelopmental disorders

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