Dual exposure-by-polygenic score interactions highlight disparities across social groups in the proportion needed to benefit

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

Published: July 30, 2024

The transferability of polygenic scores across population groups is a major concern with respect to the equitable clinical implementation genomic medicine. Since genetic associations are identified relative mean, inevitably differences in disease or trait prevalence among social strata influence relationship between PGS and risk. Here we quantify magnitude PGS-by-Exposure (PGSxE) interactions for seven human diseases (coronary artery disease, type 2 diabetes, obesity thresholded body mass index waist-to-hip ratio, inflammatory bowel chronic kidney asthma) pairs 75 exposures White-British subset UK Biobank study (n=408,801). Across 24,198 PGSxE models, 746 (3.1%) were significant by two criteria, at least three-fold more than expected chance under each criterion. Predictive accuracy significantly improved high-risk including interaction terms effects as large those documented low ancestries. predominant mechanism PGS×E shown be amplification presence adverse such polyunsaturated fatty acids, mediators obesity, determinants ill health. We introduce notion proportion needed benefit (PNB) which cumulative number treat range show that typically this halved 70

Language: Английский

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Innovation in cancer pharmacotherapy through integrative consideration of germline and tumor genomes

Pharmacological Reviews, Journal Year: 2024, Volume and Issue: 77(1), P. 100014 - 100014

Published: Oct. 15, 2024

Precision cancer medicine is widely established, and numerous molecularly targeted drugs for various tumor entities are approved or in development. Personalized pharmacotherapy oncology has so far been based primarily on characteristics, e.g., somatic mutations. However, the response to drug treatment also depends pharmacological processes summarized under term ADME (absorption, distribution, metabolism, excretion). Variations genes have subject of intensive research more than five decades, considering individual patients9 genetic makeup, referred as pharmacogenomics (PGx). The combined impact a patient9s germline genome only partially understood often not adequately considered therapy. This may be attributed, part, lack methods analysis both data layers. Optimized personalized therapies should, therefore, aim integrate molecular information about germline, taking into account existing PGx guidelines Moreover, such strategies should provide opportunity consider variants previously unknown functional significance. Bioinformatic corresponding algorithms interpretation need developed interdisciplinary boards, where patients discussed evidence-based recommendations clinical management profiles. Significance Statement era seen emergence tailored associated with biology. full potential therapy remains untapped due predominant focus acquired tumor-specific alterations. care must patient genomes, guided by pharmacogenomic principles. An essential prerequisite realizing truly development bioinformatic tools comprehensive all layers generated modern precision programs.

Language: Английский

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The NHGRI-EBI GWAS Catalog: standards for reusability, sustainability and diversity

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

Published: Oct. 23, 2024

Abstract The NHGRI-EBI GWAS Catalog serves as a vital resource for the genetic research community, providing access to most comprehensive database of human results. Currently, it contains close 7,000 publications more than 15,000 traits, from which 625,000 lead associations have been curated. Additionally, 85,000 full genome-wide summary statistics datasets - containing association data all variants in analysis are available downstream analyses such meta-analysis, fine-mapping, Mendelian randomisation or development polygenic risk scores. As centralised repository results, sets and implements standards submission harmonisation, encourages use consistent descriptors samples methodologies. We share processes vocabulary with PGS Catalog, improving interoperability growing user group. Here, we describe latest changes content, improvements our interface, implementation GWAS-SSF standard format statistics. address challenges handling rapid increase large-scale molecular quantitative trait need sensitivity population cohort while maintaining reusability.

Language: Английский

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Multi-organ imaging-derived polygenic indexes for brain and body health

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: April 20, 2023

The UK Biobank (UKB) imaging project is a crucial resource for biomedical research, but limited to 100,000 participants due cost and accessibility barriers. Here we used genetic data predict heritable imaging-derived phenotypes (IDPs) larger cohort. We developed evaluated 4,375 IDP scores (IGS) derived from UKB brain body images. When applied who were not imaged, IGS revealed links numerous stratified at increased risk both somatic diseases. For example, identified individuals higher Alzheimer's disease multiple sclerosis, offering additional insights beyond traditional polygenic of these independent external cohorts, also those high in the All Us Research Program Disease Neuroimaging Initiative study. Our results demonstrate that, while cohort largely healthy may be most enriched management, it holds immense potential stratifying various diseases broader cohorts.

Language: Английский

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Genome-wide analyses of variance in blood cell phenotypes provide new insights into complex trait biology and prediction

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

Published: April 16, 2024

Abstract Blood cell phenotypes are routinely tested in healthcare to inform clinical decisions. Genetic variants influencing mean blood have been used understand disease aetiology and improve prediction; however, additional information may be captured by genetic effects on observed variance. Here, we mapped variance quantitative trait loci (vQTL), i.e. associated with variance, for 29 from the UK Biobank (N∼408,111). We discovered 176 independent vQTLs, of which 147 were not found additive QTL mapping. vQTLs displayed average 1.8-fold stronger negative selection than QTL, highlighting that acts reduce extreme phenotypes. Variance polygenic scores (vPGSs) constructed stratify individuals INTERVAL cohort (N∼40,466), where genetically less variable (low vPGS) had increased conventional PGS accuracy (by ∼19%) more individuals. prediction traits improved ∼10% combining vPGS. Using Mendelian randomisation vPGS association analyses, alcohol consumption significantly variances utility vPGSs provide novel insight into phenotype as well prediction.

Language: Английский

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