Identifying drug targets for schizophrenia through gene prioritization DOI Creative Commons
Julia Kraft, Alice Braun, Swapnil Awasthi

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 16, 2024

Abstract Background Schizophrenia genome-wide association studies (GWASes) have identified >250 significant loci and prioritized >100 disease-related genes. However, gene prioritization efforts mostly been restricted to locus-based methods that ignore information from the rest of genome. Methods To more accurately characterize genes involved in schizophrenia etiology, we applied a combination highly-predictive tools published GWAS 67,390 cases 94,015 controls. We combined both (fine-mapped coding variants, distance signals) (PoPS, MAGMA, ultra-rare variant burden tests). validate our findings, compared them with previous efforts, known neurodevelopmental genes, results PsyOPS tool. Results 62 41 which were also highlighted by validation methods. In addition DRD2 , principal target antipsychotics, 9 are targeted approved or investigational drugs. These included drugs targeting glutamatergic receptors ( GRIN2A GRM3 ), calcium channels CACNA1C CACNB2 GABA B receptor GABBR2 ). shared an addiction e.g. PDE4B VRK2 Conclusions curated high-quality list likely play role development schizophrenia. Developing repurposing these may lead new generation therapies. Rodent models closely resemble human disorder than rodent As such, for disorders could be explored models, potentially facilitating drug development.

Language: Английский

Multimodal analysis of RNA sequencing data powers discovery of complex trait genetics DOI Creative Commons
Daniel Munro, Nava Ehsan, Seyed Mehdi Esmaeili-Fard

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Nov. 29, 2024

Abstract RNA sequencing has the potential to reveal many modalities of transcriptional regulation, such as various splicing phenotypes, but studies on gene regulation are often limited expression due complexity extracting and analyzing multiple phenotypes. Here, we present Pantry, a framework efficiently generate diverse phenotypes from data perform downstream integrative analyses with genetic data. Pantry generates six (gene expression, isoform ratios, splice junction usage, alternative TSS/polyA stability) integrates them via QTL mapping, TWAS, colocalization testing. We apply Geuvadis GTEx data, finding that 4768 genes no identified eQTL in have at least one other modality, resulting 66% increase over mapping. further found exhibit modality-specific functional properties reinforced by joint analysis different modalities. also show generalizing TWAS approximately doubles discovery unique gene-trait associations, enhances identification regulatory mechanisms underlying GWAS signal 42% previously associated pairs.

Language: Английский

Citations

1
Trans-Ancestry Analysis of Psychosis Biotypes: Shared Polygenic Risk and Unique Genomic Associations DOI Creative Commons
Elliot S. Gershon, Cuihua Xia, Ney Alliey‐Rodriguez

et al.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 29, 2024

Abstract The Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) has categorized psychosis disorders (Schizophrenia, Schizoaffective Disorder and Bipolar Disorder) into three distinct Biotypes, based on neurobiological measurements in a multi-ancestry sample. Two recently developed post hoc ancestry adjustment methods of Polygenic Risk Scores (PRSs) generate Trans-Ancestry PRSs (TAPRSs), which allow PRS analysis samples. Applied to schizophrenia PRS, we found the Khera TAPRS method show superior portability comparable prediction accuracy as compared with Ge method. Biotypes had similar TAPRSs across ancestries. In genomic nine genes isoforms showed significant associations Transcriptome-Wide Association Study (TWAS) gene expression adult brain fetal brain, isoforms. TWAS inflation was successfully controlled by inclusion genotype Principal Components association analyses. Biotype-related diagnosis distributions differ between African American European

Language: Английский

Citations

0
Exploring Gene-Mediated Mechanisms Behind Shared Phenotypes Across Diverse Diseases Using the clGENE Tool DOI Creative Commons
Zheng Li

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 12, 2024

Abstract The observation of similar clinical characteristics across a broad spectrum diseases suggests the existence underlying shared molecular mechanisms. Identifying these mechanisms is critical for uncovering roots and advancing development innovative therapeutic strategies. However, researching common genes that mediate phenotypes among different often requires integration various sequencing datasets data. batch effects complexity data present significant challenges to research. This study developed framework named “clGENE”, aimed at behind diseases. By integrating normalization, cosine similarity analysis, principal component analysis (PCA) algorithms, this capable effectively identifying associated with specific further selecting key genes. Through pan-cancer dataset, we have verified efficacy reliability “clGENE” framework. Furthermore, also established dataset on immune cell infiltration successfully identified patterns in cancer lymph node metastasis stages using ‘clGENE’ framework, confirming its potential application biomedical

Language: Английский

Citations

0
Multimodal analysis of RNA sequencing data powers discovery of complex trait genetics DOI Creative Commons
Daniel Munro, Nava Ehsan, Seyed Mehdi Esmaeili-Fard

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 15, 2024

Transcriptome data is commonly used to understand genome function via quantitative trait loci (QTL) mapping and identify the molecular mechanisms driving wide association study (GWAS) signals through colocalization analysis transcriptome-wide studies (TWAS). While RNA sequencing (RNA-seq) has potential reveal many modalities of transcriptional regulation, such as various splicing phenotypes, are often limited gene expression due complexity extracting analyzing multiple phenotypes. Here, we present Pantry (Pan-transcriptomic phenotyping), a framework efficiently generate diverse phenotypes from RNA-seq perform downstream integrative analyses with genetic data. currently generates six regulation (gene expression, isoform ratios, splice junction usage, alternative TSS/polyA stability) integrates them QTL mapping, TWAS, testing. We applied Geuvadis GTEx data, found that 4,768 genes no identified in had QTLs at least one other modality, resulting 66% increase over mapping. further exhibit modality-specific functional properties reinforced by joint different modalities. also show generalizing TWAS (xTWAS) approximately doubles discovery unique gene-trait associations, enhances identification regulatory underlying GWAS signal 42% previously associated pairs. provide code, all samples, xQTL xTWAS results on web.

Language: Английский

Citations

0
Identifying drug targets for schizophrenia through gene prioritization DOI Creative Commons
Julia Kraft, Alice Braun, Swapnil Awasthi

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 16, 2024

Abstract Background Schizophrenia genome-wide association studies (GWASes) have identified >250 significant loci and prioritized >100 disease-related genes. However, gene prioritization efforts mostly been restricted to locus-based methods that ignore information from the rest of genome. Methods To more accurately characterize genes involved in schizophrenia etiology, we applied a combination highly-predictive tools published GWAS 67,390 cases 94,015 controls. We combined both (fine-mapped coding variants, distance signals) (PoPS, MAGMA, ultra-rare variant burden tests). validate our findings, compared them with previous efforts, known neurodevelopmental genes, results PsyOPS tool. Results 62 41 which were also highlighted by validation methods. In addition DRD2 , principal target antipsychotics, 9 are targeted approved or investigational drugs. These included drugs targeting glutamatergic receptors ( GRIN2A GRM3 ), calcium channels CACNA1C CACNB2 GABA B receptor GABBR2 ). shared an addiction e.g. PDE4B VRK2 Conclusions curated high-quality list likely play role development schizophrenia. Developing repurposing these may lead new generation therapies. Rodent models closely resemble human disorder than rodent As such, for disorders could be explored models, potentially facilitating drug development.

Language: Английский

Citations

0