Identifying and correcting for misspecifications in GWAS summary statistics and polygenic scores DOI Creative Commons
Florian Privé, Julyan Arbel, Hugues Aschard

et al.

Human Genetics and Genomics Advances, Journal Year: 2022, Volume and Issue: 3(4), P. 100136 - 100136

Published: Aug. 18, 2022

Publicly available genome-wide association studies (GWAS) summary statistics exhibit uneven quality, which can impact the validity of follow-up analyses. First, we present an overview possible misspecifications that come with GWAS statistics. Then, in both simulations and real-data analyses, show additional information such as imputation INFO scores, allele frequencies, per-variant sample sizes be used to detect issues correct for One important motivation us is improve predictive performance polygenic scores built from these Unfortunately, owing lack reporting standards statistics, this not systematically reported. We also using well-matched linkage disequilibrium (LD) references model fit translate into more accurate prediction. Finally, discuss how make score methods lassosum LDpred2 robust their power.

Language: Английский

Genome-wide analysis in over 1 million individuals of European ancestry yields improved polygenic risk scores for blood pressure traits DOI Creative Commons
Jacob M. Keaton, Zoha Kamali, Tian Xie

et al.

Nature Genetics, Journal Year: 2024, Volume and Issue: 56(5), P. 778 - 791

Published: April 30, 2024

Abstract Hypertension affects more than one billion people worldwide. Here we identify 113 novel loci, reporting a total of 2,103 independent genetic signals ( P < 5 × 10 −8 ) from the largest single-stage blood pressure (BP) genome-wide association study to date n = 1,028,980 European individuals). These associations explain 60% single nucleotide polymorphism-based BP heritability. Comparing top versus bottom deciles polygenic risk scores (PRSs) reveals clinically meaningful differences in (16.9 mmHg systolic BP, 95% CI, 15.5–18.2 mmHg, 2.22 −126 and sevenfold higher odds hypertension (odds ratio, 7.33; 5.54–9.70; 4.13 −44 an dataset. Adding PRS into hypertension-prediction models increased area under receiver operating characteristic curve (AUROC) 0.791 (95% 0.781–0.801) 0.826 0.817–0.836, ∆AUROC, 0.035, 1.98 −34 ). We compare loci results non-European ancestries show significant large African-American sample. Secondary analyses implicate 500 genes previously unreported for BP. Our highlights role increasingly genomic studies precision health research.

Language: Английский

Citations

37
Leveraging functional genomic annotations and genome coverage to improve polygenic prediction of complex traits within and between ancestries DOI Creative Commons
Zhili Zheng,

Shouye Liu,

Julia Sidorenko

et al.

Nature Genetics, Journal Year: 2024, Volume and Issue: 56(5), P. 767 - 777

Published: April 30, 2024

Abstract We develop a method, SBayesRC, that integrates genome-wide association study (GWAS) summary statistics with functional genomic annotations to improve polygenic prediction of complex traits. Our method is scalable whole-genome variant analysis and refines signals from by allowing them affect both causal probability effect distribution. analyze 50 traits diseases using ∼7 million common single-nucleotide polymorphisms (SNPs) 96 annotations. SBayesRC improves accuracy 14% in European ancestry up 34% cross-ancestry compared the baseline SBayesR, which does not use annotations, outperforms other methods, including LDpred2, LDpred-funct, MegaPRS, PolyPred-S PRS-CSx. Investigation factors affecting identifies significant interaction between SNP density annotation information, suggesting sequence variants may further prediction. Functional partitioning highlights major contribution evolutionary constrained regions largest per-SNP nonsynonymous SNPs.

Language: Английский

Citations

31
Recent advances in polygenic scores: translation, equitability, methods and FAIR tools DOI Creative Commons
Ruidong Xiang, Martin Kelemen, Yu Xu

et al.

Genome Medicine, Journal Year: 2024, Volume and Issue: 16(1)

Published: Feb. 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.

Language: Английский

Citations

29
Integrative polygenic risk score improves the prediction accuracy of complex traits and diseases DOI Creative Commons
Buu Truong, Leland E. Hull, Yunfeng Ruan

et al.

Cell Genomics, Journal Year: 2024, Volume and Issue: 4(4), P. 100523 - 100523

Published: March 19, 2024

Polygenic risk scores (PRSs) are an emerging tool to predict the clinical phenotypes and outcomes of individuals. We propose PRSmix, a framework that leverages PRS corpus target trait improve prediction accuracy, PRSmix+, which incorporates genetically correlated traits better capture human genetic architecture for 47 32 diseases/traits in European South Asian ancestries, respectively. PRSmix demonstrated mean accuracy improvement 1.20-fold (95% confidence interval [CI], [1.10; 1.3]; p = 9.17 × 10

Language: Английский

Citations

28
Pleiotropy, epistasis and the genetic architecture of quantitative traits DOI
Trudy F. C. Mackay, Robert R. H. Anholt

Nature Reviews Genetics, Journal Year: 2024, Volume and Issue: 25(9), P. 639 - 657

Published: April 2, 2024

Language: Английский

Citations

28
Genetic and molecular architecture of complex traits DOI Creative Commons
Tuuli Lappalainen, Yang Li, Sohini Ramachandran

et al.

Cell, Journal Year: 2024, Volume and Issue: 187(5), P. 1059 - 1075

Published: Feb. 1, 2024

Language: Английский

Citations

21
Calibrated prediction intervals for polygenic scores across diverse contexts DOI
Kangcheng Hou,

Ziqi Xu,

Yi Ding

et al.

Nature Genetics, Journal Year: 2024, Volume and Issue: 56(7), P. 1386 - 1396

Published: June 17, 2024

Language: Английский

Citations

21
FORGEdb: a tool for identifying candidate functional variants and uncovering target genes and mechanisms for complex diseases DOI Creative Commons
Charles E. Breeze, Eric Haugen, María Gutiérrez‐Arcelus

et al.

Genome biology, Journal Year: 2024, Volume and Issue: 25(1)

Published: Jan. 2, 2024

The majority of disease-associated variants identified through genome-wide association studies are located outside protein-coding regions. Prioritizing candidate regulatory and gene targets to identify potential biological mechanisms for further functional experiments can be challenging. To address this challenge, we developed FORGEdb ( https://forgedb.cancer.gov/ ; https://forge2.altiusinstitute.org/files/forgedb.html https://doi.org/10.5281/zenodo.10067458 ), a standalone web-based tool that integrates multiple datasets, delivering information on associated elements, transcription factor binding sites, target genes over 37 million variants. scores provide researchers with quantitative assessment the relative importance each variant targeted experiments.

Language: Английский

Citations

16
Genomics yields biological and phenotypic insights into bipolar disorder DOI
Kevin S. O’Connell, Maria Koromina, Tracey van der Veen

et al.

Nature, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 22, 2025

Language: Английский

Citations

9
Clinical utility and implementation of polygenic risk scores for predicting cardiovascular disease DOI
Heribert Schunkert, Emanuele Di Angelantonio, Michael Inouye

et al.

European Heart Journal, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 5, 2025

Genome-wide association studies have revealed hundreds of genetic variants associated with cardiovascular diseases (CVD). Polygenic risk scores (PRS) can capture this information in a single metric and hold promise for use CVD prediction. Importantly, PRS reflect the causally mediated to which individual is exposed throughout life. Although European Society Cardiology guidelines do not currently advocate their routine clinical practice, are commercially available increasingly sought by clinicians, health systems, members public inform personalized care decision-making. This consensus statement provides an overview scientific basis evidence date on role prediction purposes disease prevention. It reader summary opportunities challenges implementation identifies current gaps supporting evidence. The document also lays out potential roadmap community navigate any future transition into care. Finally, scenarios presented where from may most value discuss organizational frameworks enable responsible testing while more being generated studies.

Language: Английский

Citations

6