Epigenomic partitioning of an polygenic risk score for asthma reveals distinct genetically driven disease pathways
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PROVIDER: PRJNA1028993 | ENA |
REPOSITORIES: ENA
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Project description:Background: Asthma is common chronic inflammatory disease of the airways with a heterogenous clinical presentation. Individual differences in asthma susceptibility remain poorly understood, although genetics is thought to play a major role. Aim: To build a polygenic risk score (PRS) for asthma and determine whether predictive genetic variants can be epigenomically linked to specific pathophysiological mechanisms. Methods: PRSs were constructed using data from genome-wide association studies and performance was validated using data generated in the Rotterdam Study, a Dutch prospective cohort of 14,926 individuals. Outcomes used were asthma, childhood-onset asthma, adulthood-onset asthma, eosinophilic asthma and exacerbations. Chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-Seq) data from 14 primary cell types, including lung epithelial cells and T lymphocytes was used for epigenomic PRS partitioning. Results: All PRSs successfully predicted risk to develop asthma and related outcomes, with the strongest predictive power (2.42 odds ratios per PRS standard deviation, area under the curve of 0.736) achieved for childhood-onset asthma. PRSs allowed for stratification of the Rotterdam Study cohort into groups at low or high risk to develop asthma. PRS partitioning using genome-wide epigenomic profiles identified 5 clusters of variants within gene regulatory regions linked to specific asthma-relevant cells, genes and biological pathways. Conclusions: PRSs can predict whether individuals in a Dutch cohort developed asthma and asthma-related phenotypes, which is most effective for childhood-onset asthma. Importantly, we show that PRS partitioning based on epigenomics data dissects a genetic risk score into blocks of regulatory variants with differential predictive power, which likely represent distinct genetically driven disease pathways. These findings have potential implications for personalized risk mitigation and treatment strategies.
2024-07-03 | GSE245569 | GEO
Project description:Developing a translational polygenic score of biological sensitivity to context
| PRJNA633782 | ENA
Project description:This study builds the first translational model of biological sensitivity to context. In order to determine gene expression patterns that underlie environmental responsivity, we conduct RNA sequencing of ventral dentate gyrus in C57BL6/J mice exposed to two distinctly divergent contexts: environmental enrichment or chronic social defeat stress. Differential expression analysis revealed 18 genes that were commonly regulated in response to these contexts compared to control and were thus considered environmentally responsive irrespective of the valance of the environment. Using the human orthologs, we build a polygenic score of environmental responsivity (ER-ePRS). We then tested whether this ER-ePRS moderated the relationship between the quality of the prevailing environment and anxiety-like or depression problems in four culturally distinctive human cohorts. Results reveal that the molecular underpinnings responsible for environmental responsivity in mice predict a greater propensity to develop psychopathological symptoms in humans in a context and sex dependent manner.
2020-05-20 | GSE150812 | GEO
Project description:A Polygenic Score for Acute Vaso-Occlusive Pain in Pediatric Sickle Cell Disease
| PRJNA739768 | ENA
Project description:A Polygenic Score for Acute Vaso-Occlusive Pain in Pediatric Sickle Cell Disease
| PRJNA739769 | ENA
Project description:Drug-Induced-Liver-Injury (DILI) is a leading cause of termination in drug development programs and removal of drugs from the market because of inability to identify potential patients prior to clinical testing. Here, we approached a polygenic risk score (PRS) based strategy by aggregating effects of numerous genome-wide loci identified from previous large-scale genome-wide association studies (GWAS). The PRS predicted the susceptibility to DILI in patients in a clinical trial, and in multi-donor derived primary hepatocytes and stem cell-derived organoids. Pathway analysis highlighted processes previously implicated in DILI, including unfolded protein responses and oxidative stress alleviated by a potent antioxidant. Furthermore, hepatocytic transcriptomic signatures related to polygenic score identified potential drugs with clinical DILI evidence through in silico 941 compound screening. This genetic-, cellular-, organoid- and human-scale evidence underscored the polygenic architectures underlying DILI vulnerability at the level of hepatocytes, thus facilitating future mechanistic studies. Moreover, the proposed “polygenicity-in-a-dish” strategy potentially will contribute to prospective designs of safer, more efficient, and robust clinical trials.
2020-09-07 | GSE152447 | GEO
Project description:BackgroundAsthma is the most common chronic condition in children and the third leading cause of hospitalization in pediatrics. The genome-wide association study catalog reports 140 studies with genome-wide significance. A polygenic risk score (PRS) with predictive value across ancestries has not been evaluated for this important trait.ObjectivesThis study aimed to train and validate a PRS relying on genetic determinants for asthma to provide predictions for disease occurrence in pediatric cohorts of diverse ancestries.MethodsThis study applied a Bayesian regression framework method using the Trans-National Asthma Genetic Consortium genome-wide association study summary statistics to derive a multiancestral PRS score, used one Electronic Medical Records and Genomics (eMERGE) cohort as a training set, used a second independent eMERGE cohort to validate the score, and used the UK Biobank data to replicate the findings. A phenome-wide association study was performed using the PRS to identify shared genetic etiology with other phenotypes.ResultsThe multiancestral asthma PRS was associated with asthma in the 2 pediatric validation datasets. Overall, the multiancestral asthma PRS has an area under the curve (AUC) of 0.70 (95% CI, 0.69-0.72) in the pediatric validation 1 and AUC of 0.66 (0.65-0.66) in the pediatric validation 2 datasets. We found significant discrimination across pediatric subcohorts of European (AUC, 95% CI, 0.60 and 0.66), African (AUC, 95% CI, 0.61 and 0.66), admixed American (AUC, 0.64 and 0.70), Southeast Asian (AUC, 0.65), and East Asian (AUC, 0.73) ancestry. Pediatric participants with the top 5% PRS had 2.80 to 5.82 increased odds of asthma compared to the bottom 5% across the training, validation 1, and validation 2 cohorts when adjusted for ancestry. Phenome-wide association study analysis confirmed the strong association of the identified PRS with asthma (odds ratio, 2.71, PFDR = 3.71 × 10-65) and related phenotypes.ConclusionsA multiancestral PRS for asthma based on Bayesian posterior genomic effect sizes identifies increased odds of pediatric asthma.
| S-EPMC9643615 | biostudies-literature
Project description:Leveraging large-scale datasets and single cell omics data to develop a polygenic score for cisplatin-induced ototoxicity
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Project description:Polygenic risk score for the prediction of breast cancer and terminal duct lobular unit involution of the breast
| PRJNA646550 | ENA
Project description:Polygenic risk score for the prediction of breast cancer and terminal duct lobular unit involution of the breast
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