Challenges and Opportunities for Developing More Generalizable Polygenic Risk Scores

Annual Review of Biomedical Data Science, Год журнала: 2022, Номер 5(1), С. 293 - 320

Опубликована: Май 16, 2022

Polygenic risk scores (PRS) estimate an individual's genetic likelihood of complex traits and diseases by aggregating information across multiple variants identified from genome-wide association studies. PRS can predict a broad spectrum have therefore been widely used in research settings. Some work has investigated their potential applications as biomarkers preventative medicine, but significant is still needed to definitively establish communicate absolute patients for modifiable factors demographic groups. However, the biggest limitation currently that they show poor generalizability diverse ancestries cohorts. Major efforts are underway through methodological development data generation initiatives improve generalizability. This review aims comprehensively discuss current progress on PRS, affect generalizability, promising areas improving accuracy, portability, implementation.

Язык: Английский

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Genetic architecture of the inflammatory bowel diseases across East Asian and European ancestries

Nature Genetics, Год журнала: 2023, Номер 55(5), С. 796 - 806

Опубликована: Май 1, 2023

Язык: Английский

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Recommendations on the use and reporting of race, ethnicity, and ancestry in genetic research: Experiences from the NHLBI TOPMed program

Cell Genomics, Год журнала: 2022, Номер 2(8), С. 100155 - 100155

Опубликована: Июль 26, 2022

How race, ethnicity, and ancestry are used in genomic research has wide-ranging implications for how is translated into clinical care incorporated public understanding. Correlation between race genetic contributes to unresolved complexity the scientific community, as illustrated by heterogeneous definitions applications of these variables. Here, we offer commentary recommendations on use across arc research, including data harmonization, analysis, reporting. While informed our experiences researchers affiliated with NHLBI Trans-Omics Precision Medicine (TOPMed) program, applicable basic translational diverse populations genome-wide data. Moving forward, considerable collaborative effort will be required ensure that described appropriately generate knowledge yields broad equitable benefit.

Язык: Английский

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Selection, optimization and validation of ten chronic disease polygenic risk scores for clinical implementation in diverse US populations

Nature Medicine, Год журнала: 2024, Номер 30(2), С. 480 - 487

Опубликована: Фев. 1, 2024

Polygenic risk scores (PRSs) have improved in predictive performance, but several challenges remain to be addressed before PRSs can implemented the clinic, including reduced performance of diverse populations, and interpretation communication genetic results both providers patients. To address these challenges, National Human Genome Research Institute-funded Electronic Medical Records Genomics (eMERGE) Network has developed a framework pipeline for return PRS-based genome-informed assessment 25,000 adults children as part clinical study. From an initial list 23 conditions, ten were selected implementation based on PRS medical actionability potential utility, cardiometabolic diseases cancer. Standardized metrics considered selection process, with additional consideration given strength evidence African Hispanic populations. We then (score transfer laboratory, validation verification score performance), used ancestry calibrate mean variance, utilizing genetically data from 13,475 participants All Us Program cohort train test model parameters. Finally, we created regulatory compliance report inclusion assessment. The experience eMERGE inform approach needed implement testing settings.

Язык: Английский

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Multi-ancestry study of the genetics of problematic alcohol use in over 1 million individuals

Nature Medicine, Год журнала: 2023, Номер 29(12), С. 3184 - 3192

Опубликована: Дек. 1, 2023

Abstract Problematic alcohol use (PAU), a trait that combines disorder and alcohol-related problems assessed with questionnaire, is leading cause of death morbidity worldwide. Here we conducted large cross-ancestry meta-analysis PAU in 1,079,947 individuals (European, N = 903,147; African, 122,571; Latin American, 38,962; East Asian, 13,551; South 1,716 ancestries). We observed high degree cross-ancestral similarity the genetic architecture identified 110 independent risk variants within- analyses. Cross-ancestry fine mapping improved identification likely causal variants. Prioritizing genes through gene expression chromatin interaction brain tissues multiple associated PAU. existing medications for potential pharmacological studies by computational drug repurposing analysis. polygenic scores showed better performance association samples than single-ancestry scores. Genetic correlations between other traits were ancestries, substance having highest correlations. This study advances our knowledge etiology PAU, these findings may bring possible clinical applicability genetics insights—together neuroscience, biology data science—closer.

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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Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants

Nature Genetics, Год журнала: 2023, Номер 55(12), С. 2065 - 2074

Опубликована: Ноя. 9, 2023

Язык: Английский

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A new method for multiancestry polygenic prediction improves performance across diverse populations

Nature Genetics, Год журнала: 2023, Номер 55(10), С. 1757 - 1768

Опубликована: Сен. 25, 2023

Язык: Английский

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Genetically adjusted PSA levels for prostate cancer screening

Nature Medicine, Год журнала: 2023, Номер 29(6), С. 1412 - 1423

Опубликована: Июнь 1, 2023

Abstract Prostate-specific antigen (PSA) screening for prostate cancer remains controversial because it increases overdiagnosis and overtreatment of clinically insignificant tumors. Accounting genetic determinants constitutive, non-cancer-related PSA variation has potential to improve utility. In this study, we discovered 128 genome-wide significant associations ( P < 5 × 10 −8 ) in a multi-ancestry meta-analysis 95,768 men developed polygenic score (PGS that explains 9.61% constitutive variation. We found that, European ancestry, using PGS-adjusted would avoid up 31% negative biopsies but also result 12% fewer patients with cancer, mostly Gleason <7 Genetically adjusted was more predictive aggressive (odds ratio (OR) = 3.44, 6.2 −14 , area under the curve (AUC) 0.755) than unadjusted (OR 3.31, 1.1 −12 AUC 0.738) 106 cases 23,667 controls. Compared PGS alone (AUC 0.712), including genetically improved detection disease 0.786, 7.2 −4 ). Our findings highlight utility incorporating personalized biomarkers screening.

Язык: Английский

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Leveraging functional genomic annotations and genome coverage to improve polygenic prediction of complex traits within and between ancestries

Nature Genetics, Год журнала: 2024, Номер 56(5), С. 767 - 777

Опубликована: Апрель 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.

Язык: Английский

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