Principles and methods for transferring polygenic risk scores across global populations

Nature Reviews Genetics, Год журнала: 2023, Номер 25(1), С. 8 - 25

Опубликована: Авг. 24, 2023

Язык: Английский

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Global Biobank analyses provide lessons for developing polygenic risk scores across diverse cohorts

Cell Genomics, Год журнала: 2023, Номер 3(1), С. 100241 - 100241

Опубликована: Янв. 1, 2023

Polygenic risk scores (PRSs) have been widely explored in precision medicine. However, few studies thoroughly investigated their best practices global populations across different diseases. We here utilized data from Global Biobank Meta-analysis Initiative (GBMI) to explore methodological considerations and PRS performance 9 biobanks for 14 disease endpoints. Specifically, we constructed PRSs using pruning thresholding (P + T) PRS-continuous shrinkage (CS). For both methods, a European-based linkage disequilibrium (LD) reference panel resulted comparable or higher prediction accuracy compared with several other non-European-based panels. PRS-CS overall outperformed the classic P T method, especially endpoints SNP-based heritability. Notably, is heterogeneous endpoints, biobanks, ancestries, asthma, which has known variation prevalence populations. Overall, provide lessons construction, evaluation, interpretation GBMI resources highlight importance of biobank-scale genomics era.

Язык: Английский

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Recent advances in polygenic scores: translation, equitability, methods and FAIR tools

Genome Medicine, Год журнала: 2024, Номер 16(1)

Опубликована: Фев. 19, 2024

Abstract Polygenic scores (PGS) can be used for risk stratification by quantifying individuals’ genetic predisposition to disease, and many potentially clinically useful applications have been proposed. Here, we review the latest potential benefits of PGS in clinic challenges implementation. could augment through combined use with traditional factors (demographics, disease-specific factors, family history, etc.), support diagnostic pathways, predict groups therapeutic benefits, increase efficiency clinical trials. However, there exist maximizing utility PGS, including FAIR (Findable, Accessible, Interoperable, Reusable) standardized sharing genomic data needed develop recalculate equitable performance across populations ancestries, generation robust reproducible calculations, responsible communication interpretation results. We outline how these may overcome analytically more diverse as well highlight sustained community efforts achieve equitable, impactful, healthcare.

Язык: Английский

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Improving polygenic risk prediction in admixed populations by explicitly modeling ancestral-differential effects via GAUDI

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Фев. 3, 2024

Abstract Polygenic risk scores (PRS) have shown successes in clinics, but most PRS methods focus only on participants with distinct primary continental ancestry without accommodating recently-admixed individuals mosaic backgrounds for different segments of their genomes. Here, we develop GAUDI, a novel penalized-regression-based method specifically designed admixed individuals. GAUDI explicitly models ancestry-differential effects while borrowing information across shared We demonstrate marked advantages over other through comprehensive simulation and real data analyses traits associated variants exhibiting ancestral-differential effects. Leveraging from the Women’s Health Initiative study, show that improves prediction white blood cell count C-reactive protein African Americans by > 64% compared to alternative methods, even outperforms PRS-CSx large European GWAS some scenarios. believe will be valuable tool mitigate disparities performance

Язык: Английский

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Polygenic risk alters the penetrance of monogenic kidney disease

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Дек. 14, 2023

Chronic kidney disease (CKD) is determined by an interplay of monogenic, polygenic, and environmental risks. Autosomal dominant polycystic (ADPKD) COL4A-associated nephropathy (COL4A-AN) represent the most common forms monogenic diseases. These disorders have incomplete penetrance variable expressivity, we hypothesize that polygenic factors explain some this variability. By combining SNP array, exome/genome sequence, electronic health record data from UK Biobank All-of-Us cohorts, demonstrate genome-wide score (GPS) significantly predicts CKD among ADPKD variant carriers. Compared to middle tertile GPS for noncarriers, carriers in top a 54-fold increased risk CKD, while bottom only 3-fold CKD. Similarly, COL4A-AN The 2.5-fold higher not different average population risk. results suggest accounting improves stratification disease.

Язык: Английский

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Perspectives on genetic studies of type 2 diabetes from the genome‐wide association studies era to precision medicine

Journal of Diabetes Investigation, Год журнала: 2024, Номер 15(4), С. 410 - 422

Опубликована: Янв. 23, 2024

Abstract Genome‐wide association studies (GWAS) have facilitated a substantial and rapid increase in the number of confirmed genetic susceptibility variants for complex diseases. Approximately 700 predisposing individuals to risk type 2 diabetes been identified through GWAS until 2023. From 2018 2022, hundreds loci with smaller effect sizes were large‐scale sample 200,000 >1 million. The clinical translation information includes development novel therapeutics predictions. Although drug discovery based on remains challenging owing difficulty functional annotation, global efforts made identify biological mechanisms therapeutic targets by applying multi‐omics approaches or searching disease‐associated coding isolated founder populations. Polygenic scores (PRSs), comprising up millions associated variants, can higher disease than those general population. In populations European descent, PRSs constructed from base data size approximately 450,000 predicted onset diseases well. However, GWAS‐derived limited predictive performance non‐European accuracy PRS largely depends data. results meta‐analyses multi‐ethnic groups as cross‐population polygenic prediction methodology applied establish universal applicable small ethnic

Язык: Английский

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Social-Science Genomics: Progress, Challenges, and Future Directions

Опубликована: Май 1, 2024

Rapid progress has been made in identifying links between human genetic variation and social behavioral phenotypes.Applications mainstream economics are beginning to emerge.This review aims provide the background needed bring interested economist frontier of social-science genomics.Our is structured around a theoretical framework that nests many key methods, concepts tools found literature.We clarify assumptions appropriate interpretations.After reviewing several significant applications, we conclude by outlining future advances genetics will expand scope potential discuss ethical communication challenges arise this area research.

Язык: Английский

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XMAP: Cross-population fine-mapping by leveraging genetic diversity and accounting for confounding bias

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Окт. 28, 2023

Fine-mapping prioritizes risk variants identified by genome-wide association studies (GWASs), serving as a critical step to uncover biological mechanisms underlying complex traits. However, several major challenges still remain for existing fine-mapping methods. First, the strong linkage disequilibrium among can limit statistical power and resolution of fine-mapping. Second, it is computationally expensive simultaneously search multiple causal variants. Third, confounding bias hidden in GWAS summary statistics produce spurious signals. To address these challenges, we develop method cross-population (XMAP) leveraging genetic diversity accounting bias. By using from global biobanks genomic consortia, show that XMAP achieve greater power, better control false positive rate, substantially higher computational efficiency identifying signals, compared Importantly, output be integrated with single-cell datasets, which greatly improves interpretation putative their cellular context at resolution.

Язык: Английский

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Admix-kit: an integrated toolkit and pipeline for genetic analyses of admixed populations

Bioinformatics, Год журнала: 2024, Номер 40(4)

Опубликована: Март 15, 2024

Abstract Summary Admixed populations, with their unique and diverse genetic backgrounds, are often underrepresented in studies. This oversight not only limits our understanding but also exacerbates existing health disparities. One major barrier has been the lack of efficient tools tailored for special challenges studies admixed populations. Here, we present admix-kit, an integrated toolkit pipeline analyses Admix-kit implements a suite methods to facilitate genotype phenotype simulation, association testing, architecture inference, polygenic scoring Availability implementation package is open-source available at https://github.com/KangchengHou/admix-kit. Additionally, users can use designed simulation https://github.com/UW-GAC/admix-kit_workflow.

Язык: Английский

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Leveraging fine-scale population structure reveals conservation in genetic effect sizes between human populations across a range of human phenotypes

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

Опубликована: Авг. 9, 2023

Abstract An understanding of genetic differences between populations is essential for avoiding confounding in genome-wide association studies (GWAS) and the evolution human traits. Polygenic risk scores constructed one group perform poorly highly genetically-differentiated populations, reasons which remain controversial. We developed a statistical ancestry inference pipeline able to decompose both within countries, applied it UK Biobank data. This identifies fine-scale patterns relatedness not captured by standard widely used principal components (PCs), allows population stratification correction that removes false positive negative associations traits with geographic correlations. also develop apply ANCHOR, an approach leveraging segments distinct ancestries individuals estimate similarity underlying causal effect sizes groups, using existing PGS. Applying ANCHOR >8000 people mixed African European ancestry, we demonstrate estimated are similar across these 26 29 quantitative molecular non-molecular phenotypes (mean correlation 0.98 +/-0.08), providing evidence gene-environment gene-gene interactions do play major roles poor prediction European-ancestry PRS traits, contradicting previous findings. Instead our results provide optimism shared mutations operate similarly different focussing challenge improving GWAS “portability” groups on joint fine-mapping.

Язык: Английский

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