Transcriptome‐Wide Association Studies (TWAS): Methodologies, Applications, and Challenges

Current Protocols, Год журнала: 2024, Номер 4(2)

Опубликована: Фев. 1, 2024

Abstract Transcriptome‐wide association study (TWAS) methodologies aim to identify genetic effects on phenotypes through the mediation of gene transcription. In TWAS, in silico models expression are trained as functions variants and then applied genome‐wide (GWAS) data. This post‐GWAS analysis identifies gene‐trait associations with high interpretability, enabling follow‐up functional genomics studies development genetics‐anchored resources. We provide an overview commonly used TWAS approaches, their advantages limitations, some widely applications. © 2024 Wiley Periodicals LLC.

Язык: Английский

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Sex-Differential Gene Expression in Developing Human Cortex and Its Intersection With Autism Risk Pathways

Biological Psychiatry Global Open Science, Год журнала: 2024, Номер 4(4), С. 100321 - 100321

Опубликована: Апрель 26, 2024

Sex-differential biology may contribute to the consistently male-biased prevalence of autism spectrum disorder (ASD). Gene expression differences between males and females in brain can indicate possible molecular cellular mechanisms involved, though transcriptomic sex during human prenatal cortical development have been incompletely characterized, primarily due small sample sizes. We performed a meta-analysis sex-differential co-expression network analysis two independent bulk RNA-seq data sets generated from cortex 273 donors without known neuropsychiatric disorders. To assess intersection neurotypical biology, we tested for enrichment ASD-associated risk genes changes, genes, cell type markers within identified sex-differentially expressed (sex-DEGs) modules. identify 101 significant sex-DEGs, including Y chromosome impacted by X inactivation, autosomal genes. Known ASD implicated either common or rare variants, do not preferentially overlap with sex-DEGs. one male-specific module enriched immune signaling that is unique input set. gene limited tissue, large allows identification encode proteins involved neural development. Lack sex-DEG suggests modulation symptoms occur other regions, developmental stages, specific types, involve acting downstream mutation-carrying

Язык: Английский

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Genomics yields biological and phenotypic insights into bipolar disorder

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Окт. 7, 2023

Abstract Bipolar disorder (BD) is a leading contributor to the global burden of disease 1 . Despite high heritability (60-80%), majority underlying genetic determinants remain unknown 2 We analysed data from participants European, East Asian, African American and Latino ancestries (n=158,036 BD cases, 2.8 million controls), combining Clinical, Community, Self-reported samples. identified 298 genome-wide significant loci in multi-ancestry meta-analysis, 4-fold increase over previous findings 3 , novel ancestry-specific association Asian cohort. Integrating results fine-mapping other variant-to-gene mapping approaches 36 credible genes aetiology BD. Genes prioritised through were enriched for ultra-rare damaging missense protein-truncating variations cases 4 highlighting convergence common rare variant signals. report differences architecture depending on source patient ascertainment BD-subtype (BDI BDII). Several analyses implicate specific cell types pathophysiology, including GABAergic interneurons medium spiny neurons. Together, these provide insights into biological underpinnings

Язык: Английский

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webTWAS 2.0: update platform for identifying complex disease susceptibility genes through transcriptome-wide association study

Nucleic Acids Research, Год журнала: 2024, Номер 53(D1), С. D1261 - D1269

Опубликована: Ноя. 11, 2024

Transcriptome-wide association study (TWAS) has successfully identified numerous complex disease susceptibility genes in the post-genome-wide (GWAS) era. Over past 3 years, focus of TWAS algorithms shifted from merely identifying associations to understanding how single nucleotide polymorphisms (SNPs) regulate gene expression, with a growing emphasis on incorporating fine-mapping techniques. Additionally, rapid increase GWAS summary statistics, driven largely by UK Biobank and other consortia, made it essential update our webTWAS resource. To address these challenges meet needs researchers, we developed 2.0, an updated platform for human diseases using TWAS. 2.0 provides online analysis tool that simplifies conducting analyses. The resource includes 7247 statistics covering 1588 192 publications. It also incorporates multiple methods, such as sTF-TWAS, 3'aTWAS GIFT, along interactive visualization allows users easily explore significant across different methods. Other upgrades include personalized user-submitted data refined search function makes easier identify relevant diverse user more efficiently. is freely accessible at http://www.webtwas.net.

Язык: Английский

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On the problem of inflation in transcriptome-wide association studies

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Окт. 20, 2023

Abstract Transcription-wide association studies (TWAS) and related methods (xWAS) have been widely adopted in genetic to understand molecular traits as mediators between variation disease. However, the effect of polygenicity on validity these mediator–trait tests has largely overlooked. Given widespread complex traits, it is necessary assess accuracy tests. We found that for highly polygenic target standard test based linear regression inflated, leading greatly increased false positives rates, especially large sample sizes. Here, we show extent inflation a function underlying GWAS size heritability trait. To address this inflation, propose an effective variance control method, similar genomic control, but which allows different correction factor each gene. Using simulated real data, well theoretical derivations, our method yields calibrated positive outperforming existing approaches. further demonstrate analogous TWAS associate predictors mediating with suffer from issues. advise developers (including risk scores, PRS) compute provide parameters ensure proper control. Finally, updated PrediXcan software package resources facilitate end users.

Язык: Английский

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Dynamic convergence of autism disorder risk genes across neurodevelopment

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Авг. 24, 2024

Over a hundred risk genes underlie for autism spectrum disorder (ASD) but the extent to which they converge on shared downstream targets increase ASD is unknown. To test hypothesis that cellular context impacts nature of convergence, here we apply pooled CRISPR approach target 29 loss-of-function in human induced pluripotent stem cell (hiPSC)-derived neural progenitor cells, glutamatergic neurons, and GABAergic neurons. Two distinct approaches (gene-level network-level analyses) demonstrate convergence greatest mature Convergent effects are dynamic, varying strength, composition, biological role between types, increasing with functional similarity examined, driven by cell-type-specific gene co-expression patterns. Stratification yield targeted drug predictions capable reversing gene-specific convergent signatures cells ASD-related behaviors zebrafish. Altogether, networks represent novel points individualized therapeutic intervention.

Язык: Английский

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Genetic analysis of psychosis Biotypes: shared Ancestry-adjusted polygenic risk and unique genomic associations

Molecular Psychiatry, Год журнала: 2024, Номер unknown

Опубликована: Дек. 21, 2024

Язык: Английский

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Accounting for isoform expression increases power to identify genetic regulation of gene expression

PLoS Computational Biology, Год журнала: 2024, Номер 20(2), С. e1011857 - e1011857

Опубликована: Фев. 12, 2024

A core problem in genetics is molecular quantitative trait locus (QTL) mapping, which genetic variants associated with changes the phenotypes are identified. One of most-studied QTL mapping problems expression (eQTL) phenotype gene expression. It common eQTL to compute by aggregating levels individual isoforms from same and then performing linear regression between SNPs this aggregated level. However, may regulate different directions due alternative splicing, or only level one isoform, causing approach lose power. Here, we examine a broader question: genes have at least isoform whose regulated variants? In study, propose evaluate several approaches answering question, demonstrating that “isoform-aware” methods—those account for isoforms—have substantially greater power answer question than standard “gene-level” methods. We identify settings yield an inflated number false discoveries particular, show calling eGene if there significant association SNP any fails control False Discovery Rate, even when applying Rate correction. similar trends observed real data GEUVADIS GTEx studies, suggesting possibility effects present these consortia.

Язык: Английский

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Circadian clocks in human cerebral organoids

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Фев. 21, 2024

Summary Circadian rhythms result from cell-intrinsic timing mechanisms that impact health and disease 1,2 . To date, however, neural circadian research has largely focused on the hypothalamic circuitry of nocturnal rodents 3 Whether exist in human brain cells is unknown. Here we show bona fide neurons, glia, cerebral organoids, organoid slices (ALI-COs) 4–8 Human are synchronised by physiological cues such as glucocorticoids daily temperature cycles, these temperature-compensated across range normal temperatures 9 Astrocyte phase-advanced relative to other cultures they modulate neuronal clock responses shift. Cerebral more robust at temperatures; amplitude increases over time culture their resetting capacity recapitulates key neurodevelopmental transitions glucocorticoid signalling 10–14 Remarkably, post-transcriptional bioluminescent reporter retained even when those putative transcriptional drivers indiscernible 15 , electrophysiology recordings confirm functional activity monocultures, ALI-COs. Around one third proteome phosphoproteome circadian-rhythmic, with temporal consolidation disease-relevant processes. Finally, can be modulated disrupted commonly used brain-permeant drugs mistimed cortisol exposure, respectively. Our results demonstrate tissues develop own oscillations canonical clockwork may inadequate explain rhythmic phenomena. 2D 3D represent complementary tractable models for exploring emergence, disruption, mechanics clockwork, important implications chronobiology, function, health.

Язык: Английский

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Dissecting Schizophrenia Biology Using Pleiotropy with Cognitive Genomics

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Апрель 16, 2024

Abstract Given the increasingly large number of loci discovered by psychiatric GWAS, specification key biological pathways underlying these has become a priority for field. We have previously leveraged pleiotropic genetic relationships between schizophrenia and two cognitive phenotypes (educational attainment task performance) to differentiate subsets illness-relevant SNPs: (1) those with “concordant” alleles, which are associated reduced ability/education increased risk; (2) “discordant” alleles linked educational and/or levels but lower susceptibility. In present study, we extend our prior work, utilizing larger input GWAS datasets more powerful statistical approach meta-analysis, Pleiotropic Locus Exploration Interpretation using Optimal test (PLEIO). Our meta-analysis revealed 768 significant (159 novel). Among these, 347 harbored concordant SNPs, 270 encompassed discordant 151 “dual” contained SNPs. Competitive gene-set analysis MAGMA related SNP neurodevelopmental (e.g., neurogenesis), whereas were mature neuronal synaptic functions. These distinctions also observed in BrainSpan temporal enrichment patterns across developmental periods, containing prenatally expressed genes than loci. Dual enriched mRNA translation initiation, representing novel finding literature.

Язык: Английский

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