294 hot topic(s) found with the query "Genetic risk score"
Age and Genetic Risk Score and Rates of Blood Lipid Changes in China.
Jianxin Li et al. JAMA network open 2023 3 (3) e235565
(Posted: Mar-31-2023 6AM)
Are age and genetic risk associated with rates of blood lipid changes among adults in China? In this cohort study of 37?317 participants, the estimated annual changes of blood lipids were associated with age and polygenic risk. Moreover, the associations of the estimated annual lipid changes with age differed significantly between male and female participants. These findings suggest that strategies for precision management of lipid levels should focus on individuals at high genetic risk and in the critical age window.
Genome-based scores predict thousands of molecular traits in humans.
et al. Nature 2023 3
(Posted: Mar-30-2023 8AM)
Genetic scores for predicting levels of several types of biomolecule have been developed and validated in people of diverse ancestries, and used to uncover insights into disease biology. An open resource to disseminate these scores, OmicsPred, will enable researchers to predict various molecular traits from genetic profiles in their own data sets.
Laboratory perspectives in the development of polygenic risk scores for disease: A points to consider statement of the American College of Medical Genetics and Genomics (ACMG).
Honey V Reddi et al. Genetics in medicine : official journal of the American College of Medical Genetics 2023 3 100804
(Posted: Mar-28-2023 6AM)
This Points to Consider document will (1) provide general consideration for PRS-based genetic tests, (2) outline considerations for the laboratory implementing such tests, (3) recommend appropriate criteria for reporting of PRS, and (4) define and disclose the scope and limitations of such tests.
ACMG statement on clinical application of polygenic risk scores
L Blackburn, PHG Foundation Blog, March 2023
(Posted: Mar-27-2023 7AM)
When it comes to implementing polygenic scores into routine healthcare, there are many questions yet to be answered - how polygenic scores are going to be used, is the intention to use them for all conditions or just specific ones, are they to answer questions around diagnosis or prediction? Or both? Only when answers to these and similar questions have been articulated can robust standards for evidence generation and assessment be developed.
Polygenic Scores in the Direct-to-Consumer Setting: Challenges and Opportunities for a New Era in Consumer Genetic Testing
JK Park et al, J Per Med, March 23, 2023
(Posted: Mar-23-2023 7AM)
While PGS have thus far been extensively explored as clinical and public health tools, the use of PGS in consumer genetic testing has not yet received systematic attention, even though they are already in use for some consumer genetic tests. In this narrative review, we highlight the ethical, legal, and social implications of the use of PGS in DTC genetic tests and synthesize existing solutions to these concerns.
The clinical application of polygenic risk scores: A points to consider statement of the American College of Medical Genetics and Genomics (ACMG).
Aya Abu-El-Haija et al. Genetics in medicine : official journal of the American College of Medical Genetics 2023 3 100803
(Posted: Mar-17-2023 5PM)
Although being rapidly incorporated into health care, there are currently no clinical guidelines available for the use of this technology. PRSs are probabilities and do not directly provide an absolute risk for disease development. PRS provides the relative risk of developing a disease and should be used as an adjunct tool to determine the likelihood of developing a specific disorder. Prospective studies are needed to determine if a given PRS result paired with a specific preventative measure leads to better clinical outcomes.
Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk.
Nick Shrine et al. Nature genetics 2023 3 (3) 410-422
(Posted: Mar-15-2023 6PM)
Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by =2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups.
Validation of a Polygenic Score for Beta-Blocker Survival Benefit in Patients With Heart Failure Using the United Kingdom Biobank.
David E Lanfear et al. Circulation. Genomic and precision medicine 2023 3 e003835
(Posted: Mar-04-2023 9AM)
Integration of a Cross-Ancestry Polygenic Model With Clinical Risk Factors Improves Breast Cancer Risk Stratification.
Placede T Tshiaba et al. JCO precision oncology 2023 2 e2200447
(Posted: Mar-03-2023 4PM)
We used diverse retrospective cohort data with longitudinal follow-up to develop a caPRS and integrate it with the Tyrer-Cuzick (T-C) clinical model. We tested the association between the caIRS and BC risk in two validation cohorts including > 130,000 women. Adding a caPRS to the T-C model improves BC risk stratification for women of multiple ancestries, which could have implications for screening recommendations and prevention.
The necessity of incorporating non-genetic risk factors into polygenic risk score models
S van Dam et al, Sci Reports, February 20, 2023
(Posted: Feb-20-2023 8AM)
The growing public interest in genetic risk scores for various health conditions can be harnessed to inspire preventive health action. However, current commercially available genetic risk scores can be deceiving as they do not consider other, easily attainable risk factors, such as sex, BMI, age, smoking habits, parental disease status and physical activity. We show improved performance at identifying the 10% most at-risk individuals for type 2 diabetes (T2D) and coronary artery disease (CAD) by including common risk factors.
Perceived benefits and barriers to implementing precision preventive care: Results of a national physician survey
JL Vassy et al, EJHG, February 20, 2023
(Posted: Feb-20-2023 7AM)
Among 367 respondents (participation rate 96.3%), mean (SD) age was 54.9 (12.9) years, 137 (37.3%) were female, and mean (SD) time since medical school graduation was 27.2 (13.3) years. Respondents reported greater perceived utility for more clinical action (e.g., earlier or more intensive screening, preventive medications, or lifestyle modification) for patients with high-risk PRS than for delayed or discontinued prevention actions for low-risk patients (p?<?0.001). Respondents most often chose out-of-pocket costs (48%), lack of clinical guidelines (24%), and insurance discrimination concerns (22%) as extreme barriers.
Re-envisioning community genetics: community empowerment in preventive genomics
H Wand et al, J Comm Genetics, February 11, 2023
(Posted: Feb-14-2023 7AM)
This paper argues that any conversation about whether and how to design and implement polygenic risk scores (PGS) clinical services requires dynamic engagement with local communities, patients, and families. These parties often face the consequences, both positive and negative, of such uncertainties and should therefore drive clinical translation. As a collaborative effort between hospital stakeholders, community partners, and researchers, this paper describes a community-empowered co-design process for addressing uncertainty and making programmatic decisions about the implementation of PGS into clinical services.
Public views on polygenic screening of embryos.
Michelle N Meyer et al. Science (New York, N.Y.) 2023 2 (6632) 541-543
(Posted: Feb-14-2023 7AM)
Seeing gaps in evidence and analysis relevant for potential policy discussions around PGT-P, we conducted a survey of public attitudes. Our data suggest that it would be unwise to assume that use of PGT-P—even for controversial traits—will be limited to idiosyncratic individuals, or that it has little potential to cause or contribute to society-wide changes and inequities.
Primary care physician use of patient race and polygenic risk scores in medical decision-making
BJ Kerman et al, Genetics in Medicine, February 6, 2023
(Posted: Feb-06-2023 9AM)
The use of patient race in medicine is controversial for its potential either to exacerbate or address health disparities. Polygenic risk scores (PRS) have emerged as a tool for risk stratification models used in preventive medicine. We examined whether PRS results impact primary care physician (PCP) medical decision-making and whether that impact varies by patient race. The study shows that despite advances in precision risk stratification, physicians will likely continue to use patient race implicitly or explicitly in medical decision-making.
Genomics and phenomics of body mass index reveals a complex disease network.
Huang Jie et al. Nature communications 2022 12 (1) 7973
(Posted: Jan-02-2023 0PM)
Using a BMI genetic risk score including 2446 variants, 316 diagnoses are associated in the Million Veteran Program, with 96.5% showing increased risk. A co-morbidity network analysis reveals seven disease communities containing multiple interconnected diseases associated with BMI as well as extensive connections across communities. Mendelian randomization analysis confirms phenotypes across many organ systems, including conditions of the circulatory (heart failure, ischemic heart disease, atrial fibrillation), genitourinary (chronic renal failure), respiratory (respiratory failure, asthma), musculoskeletal and dermatologic systems.
Cardiovascular Disease Risk Prediction in Young Adults—The Next Frontier
SS Khan et al, JAMA Cardiology, December 28, 2022
(Posted: Dec-28-2022 0PM)
A recent study highlights the need to focus on risk prediction in younger adults. This warrants a life course perspective that incorporates both lifetime risk and expected treatment benefit. Before considering the addition of PRS in the subset of individuals aged 40 to 49 years with borderline to intermediate risk, strategies for risk estimation should rigorously evaluate clinical utility of 30-year risk assessment based on traditional risk factors, dynamic changes in risk factor levels, and causal factors (apolipoprotein B, lipoprotein[a]).
Predictive Utility of a Coronary Artery Disease Polygenic Risk Score in Primary Prevention
NA Marston et al, JAMA Cardiology, December 28, 2022
(Posted: Dec-28-2022 0PM)
In this cohort study of 330?201 patients, a PRS for CAD carried significantly greater predictive power in younger adults, contributing up to 30% of the myocardial infarction risk in this cohort. Younger adults with borderline and intermediate clinical risk but high polygenic risk for CAD were significantly reclassified into a risk category for which statin therapy is indicated. Although not necessary in all individuals, a targeted approach to CAD PRS testing may help guide preventive strategies such as statin initiation in younger adults with borderline to intermediate cardiovascular risk.
Ethical, legal, and social implications of genetic risk prediction for multifactorial disease: a narrative review identifying concerns about interpretation and use of polygenic scores
CR Chapman, J Comm Genetics, December 19, 2022
(Posted: Dec-22-2022 9AM)
There is significant interest in using genetic risk prediction afforded through PGS in public health, clinical care, and research settings, yet many acknowledge the need to thoughtfully consider and address ethical, legal, and social implications (ELSI). Ninety-two articles, spanning from 1977 to 2021, met the inclusion criteria for this study. Identified ELSI included potential benefits, challenges and risks that focused on concerns about interpretation and use, and ethical obligations to maximize benefits, minimize risks, promote justice, and support autonomy.
Addressing the challenges of polygenic scores in human genetic research
J Novembre et al, AJHG, December 1, 2022
(Posted: Dec-02-2022 11AM)
Although the quantity and quality of data to compute PGSs are increasing, challenges remain in the technical aspects of developing PGSs and in the ethical and social issues that might arise from their use. This ASHG Guidance emphasizes three major themes for researchers working with or interested in the application of PGSs in their own research: (1) developing diverse research cohorts; (2) fostering robustness in the development, application, and interpretation of PGSs; and (3) improving the communication of PGS results and their implications to broad audiences.
Cancer, screening, and polygenic scores
C Babb de Villiers, PHG Foundation blog, November 1, 2022
(Posted: Nov-03-2022 11AM)
The use of comprehensive risk prediction models that include genetic, environmental and lifestyle risk factors, are being trialled for stratified screening programmes. The results from these trials are imminent in the next few years and when they arrive they will provide evidence on whether risk prediction using polygenic scores can improve risk prediction for cancer and contribute towards stratified screening.
Models of communication for polygenic scores and associated psychosocial and behavioral effects on recipients: A systematic review.
Wallingford Courtney K et al. Genetics in medicine : official journal of the American College of Medical Genetics 2022 11
(Posted: Nov-03-2022 8AM)
In total, 28 articles, representing 17 studies in several disease settings were identified. There was limited consistency in PGS communication and evaluation/reporting of outcomes. Most studies (n = 14) presented risk in multiple ways (ie, numerically, verbally, and/or visually). Three studies provided personalized lifestyle advice and additional resources. Only 1 of 17 studies reported using behavior change theory to inform their PGS intervention.
Our findings call for development of best communication practices and evidence-based interventions informed by behavior change theories.
A combined polygenic score of 21,293 rare and 22 common variants improves diabetes diagnosis based on hemoglobin A1C levels
P Dornbos et al, Nature Genetics, October 24, 2022
(Posted: Oct-25-2022 10AM)
We developed a method for constructing rare variant PGSs and applied it to calculate genetically modified hemoglobin A1C thresholds for type 2 diabetes (T2D) diagnosis7,8,9,10. The resultant rare variant PGS is highly polygenic (21,293 variants across 154 genes), depends on ultra-rare variants (72.7% observed in fewer than three people) and identifies significantly more undiagnosed T2D cases than expected by chance (odds ratio?=?2.71; P?=?1.51?×?10-6). A PGS combining common and rare variants is expected to identify 4.9?million misdiagnosed T2D cases in the United States.
Patient and provider perspectives on polygenic risk scores: implications for clinical reporting and utilization.
Lewis Anna C F et al. Genome medicine 2022 10 (1) 114
(Posted: Oct-09-2022 11AM)
Many patients did not understand the numbers representing risk, with high numeracy patients being the exception. However, all the patients still understood a key takeaway that they should ask their PCP about actions to lower their disease risk. PCPs described a diverse range of heuristics they would use to interpret and act on PRS information. PCPs saw PRS information as a natural extension of their current practice. The most pressing gap for PRS implementation is evidence for clinical utility. Careful clinical report design can help ensure that benefits are realized and harms are minimized.
Polygenic scores for cancer
The PHG Foundation, September 2022
(Posted: Oct-06-2022 9AM)
The report provides an overview of what is known about polygenic scores - when multiple genetic variants associated with a disease are combined - and what they could mean for cancer prediction, prevention and management. This accessible short report for health policy makers and other stakeholders also sets out the potential areas where implementation into health services is being considered and outlines current gaps in the scientific evidence.
A qualitative study exploring the consumer experience of receiving self-initiated polygenic risk scores from a third-party website
K Lowes et al, EJHG, October 4, 2022
(Posted: Oct-04-2022 8AM)
Dissatisfaction with healthcare was an important motivator for seeking PRS information. Participants described having medical concerns dismissed and experiencing medical distrust, which drove them to self-advocate for their health, which ultimately led them to seek PRSs. Polygenic risk scores were often empowering for participants but could be distressing when PRS information did not align with participants’ perceptions of their personal or family histories.
Polygenic scoring accuracy varies across the genetic ancestry continuum in all human populations
Y Ding et al, BIORXIV, September 29, 2022
(Posted: Sep-30-2022 6AM)
We show that PGS accuracy varies between individuals across the genetic ancestry continuum in all ancestries, even within traditionally "homogeneous" genetic ancestry clusters. Using a large and diverse Los Angeles biobank (ATLAS, N= 36,778) along with the UK Biobank (UKBB, N= 487,409), we show that PGS accuracy decreases along a continuum of genetic ancestries in all considered populations and the trend is well-captured by a continuous measure of genetic distance (GD) from the PGS training data.
The controversial embryo tests that promise a better baby Some companies offer tests that rank embryos based on their risk of developing complex diseases such as schizophrenia or heart disease. Are they accurate — or ethical?
M Koslov, Nature, September 21, 2022
(Posted: Sep-22-2022 6AM)
Pre-implantation genetic testing (PGT) for rare genetic disorders and chromosomal abnormalities has become common practice in the US$14-billion IVF industry. But testing for polygenic conditions (often referred to as PGT-P) is much newer, with only a small handful of companies selling it in a few countries, including the United States and Brazil, where it is largely unregulated.
Educational considerations based on medical student use of polygenic risk information and apparent race in a simulated consultation.
Hollister Brittany M et al. Genetics in medicine : official journal of the American College of Medical Genetics 2022 9
(Posted: Sep-05-2022 6AM)
Medical students (N = 84) were randomized to a simulated primary care encounter with a Black or White virtual reality–based patient and received either a direct-to-consumer–style PRS report for 5 common complex conditions or control information. When medical students received PRSs, they rated the patient as less healthy and requiring more strict advice. Patterns suggest that PRSs influenced specific medical recommendations related to the patient’s concerns, despite student reports that participants did not use it for that purpose.
Broad clinical manifestations of polygenic risk for coronary artery disease in the Women’s Health Initiative
SL Clarke et al, Comm Medicine, August 25, 2022
(Posted: Aug-26-2022 8AM)
Polygenic risk for CAD is associated with a variety of biomarkers, clinical measurements, behaviors, and diagnoses related to traditional risk factors, as well as risk-enhancing factors. Analysis of adjudicated outcomes shows a graded association between atherosclerosis related outcomes, with the highest odds ratios being observed for the most severe manifestations of CAD. We find associations between increased polygenic risk for CAD and decreased risk for incident breast and lung cancer, with replication of the breast cancer finding in an external cohort.
Incremental Value of Polygenic Risk Scores in Primary Prevention of Coronary Heart Disease A Review
JW Gronedick et al, JAMA Internal Medicine, August 22, 2022
(Posted: Aug-22-2022 4PM)
In this review, polygenic risk scores were significantly associated with CHD risk in all studies. The degree of improvement in C statistic and the net reclassification indexes when PRS was added to traditional risk scores ranged from negligible to modest. Based on established metrics to assess risk prediction scores, the addition of PRS to traditional risk scores does not appear to provide meaningful improvements in clinical decision-making in primary prevention populations.
Genetic risk score enhances the risk prediction of severe obesity in adult survivors of childhood cancer.
Sapkota Yadav et al. Nature medicine 2022 7
(Posted: Jul-26-2022 7AM)
We show the contribution of genetic risk scores (GRSs) to increase prediction of those survivors of childhood cancer who are at risk for severe obesity (body mass index =40?kg?m-2) as an adult. Among 2,548 individuals of European ancestry from the St. Jude Lifetime Cohort Study who were 5-year survivors of childhood cancer, the GRS was found to be associated with 53-fold-higher odds of severe obesity. Addition of GRSs to risk prediction models based on cancer treatment exposures and lifestyle factors significantly improved model prediction (area under the curve increased from 0.68 to 0.75, resulting in the identification of 4.3-times more high-risk survivors).
Re-envisioning Community Genetics: Community Empowerment in Preventive Genomics
H Wand et al, Research Square, July 19, 2022
(Posted: Jul-20-2022 7AM)
his paper argues that any conversation about whether and how to design and implement PGS clinical services requires dynamic engagement with local communities, patients, and families. These parties often face the consequences, both positive and negative, of such uncertainties and should therefore drive clinical translation. As a collaborative effort between hospital stakeholders, community partners, and researchers, this paper describes a community-empowered co-design process for addressing uncertainty and making programmatic decisions about the implementation of PGS into clinical services.
Polygenic Risk Scores for Cardiovascular Disease: A Scientific Statement From the American Heart Association
JW O'Sullivan et al, Circulation, July 18, 2022
(Posted: Jul-18-2022 1PM)
Individuals and their physicians are increasingly presented with polygenic risk scores for cardiovascular conditions in clinical encounters. In this scientific statement, we review the contemporary science, clinical considerations, and future challenges for polygenic risk scores for cardiovascular diseases. We selected 5 cardiometabolic diseases (coronary artery disease, hypercholesterolemia, type 2 diabetes, atrial fibrillation, and venous thromboembolic disease) and response to drug therapy and offer provisional guidance to health care professionals, researchers, policymakers, and patients.
Incorporating family history of disease improves polygenic risk scores in diverse populations
MLA Hujeol et al, Cell Genomics, July 13, 2022
(Posted: Jul-14-2022 7AM)
Polygenic risk scores (PRSs) derived from genotype data and family history (FH) of disease provide valuable information for predicting disease risk, but PRSs perform poorly when applied to diverse populations. Here, we explore methods for combining both types of information (PRS-FH) in UK Biobank data. We evaluated PRS, FH, and PRS-FH using liability-scale R2, primarily focusing on 3 well-powered diseases (type 2 diabetes, hypertension, and depression). PRS attained average prediction R2s of 5.8%, 4.0%, and 0.53% in non-British Europeans, South Asians, and Africans, confirming poor cross-population transferability. In contrast, PRS-FH attained average prediction R2s of 13%, 12%, and 10%, respectively, representing a large improvement in Europeans and an extremely large improvement in Africans. In conclusion, including family history improves the accuracy of polygenic risk scores, particularly in diverse populations.
Polygenic Risk Scores in Clinical Practice? Still Making the Case
J Osei et al, CDC Blog Post, July 5, 2022
(Posted: Jul-05-2022 3PM)
Two recent systematic reviews show the lack of data on clinical utility of polygenic risk scores and major challenges in implementation. Multiple studies have explored the use of PRS in risk stratification, screening, prediction and treatment of chronic diseases. However, to date there has not been strong evidentiary support for their routine use in clinical and public health practice. We still do not know how best to integrate this PRS into health care.
Transferability of genetic risk scores in African populations
AB Kamiza et al, Nature Medicine, June 2, 2022
(Posted: Jun-03-2022 10AM)
Using summary statistics from the Million Veteran Program (MVP), we showed that GRSs derived from data of African American individuals enhance polygenic prediction of lipid traits in SSA compared to European and multiancestry scores. However, our GRS prediction varied greatly within SSA between the South African Zulu (low-density lipoprotein cholesterol (LDL-C), R2?=?8.14%) and Ugandan cohorts (LDL-C, R2?=?0.026%). We postulate that differences in the genetic and environmental factors between these population groups might lead to the poor transferability of GRSs within SSA. More effort is required to optimize polygenic prediction in Africa.
Polygenic risk scores to stratify cancer screening should predict mortality not incidence
AJ Vickers et al, NPJ Precision Oncology, May 30, 2022
(Posted: Jun-01-2022 7AM)
It has recently been proposed that cancer screening could be restricted to a high-risk subgroup based on polygenic risk scores (PRSs) using panels of single-nucleotide polymorphisms (SNPs). These PRSs were, however, generated to predict cancer incidence rather than cancer mortality and will not necessarily address overdiagnosis, a major problem associated with cancer screening programs.
Integration of rare expression outlier-associated variants improves polygenic risk prediction
C Smail et al, AJHG, May 18, 2022
(Posted: May-19-2022 10AM)
Polygenic risk scores (PRSs) quantify the contribution of multiple genetic loci to an individual’s likelihood of a complex trait or disease. However, existing PRSs estimate this likelihood with common genetic variants, excluding the impact of rare variants. Here, we report on a method to identify rare variants associated with outlier gene expression and integrate their impact into PRS predictions for body mass index (BMI), obesity, and bariatric surgery. Between the top and bottom 10%, we observed a 20.8% increase in risk for obesity (p = 3 × 10-14), 62.3% increase in risk for severe obesity (p = 1 × 10-6), and median 5.29 years earlier onset for bariatric surgery (p = 0.008), as a function of expression outlier-associated rare variant burden when controlling for common variant PRS.
Can polygenic risk scores contribute to cost-effective cancer screening? A systematic review
P Dixon et al, Genetics in Medicine, May 16, 2022
(Posted: May-16-2022 10AM)
Despite the positive conclusions of the studies included in this systematic review, it is unclear if polygenic risk stratification will contribute to cost-effective cancer screening given the absence of robust evidence on the costs of polygenic risk stratification, the effects of differential ancestry, potential downstream economic sequalae, and how large volumes of polygenic risk data would be collected and used.
Polygenic scores - from risk models to clinical assays
S Moorthie, PHG Foundation, May 12, 2022
(Posted: May-12-2022 10AM)
There is a lot of enthusiasm for using polygenic scores as a biomarker within healthcare pathways, but, as with other biomarkers, they don’t provide a complete solution, nor do they provide definitive answers. We still need to develop the evidence-base for its use within specified care pathways. There also needs to be clarity about what the information from such analysis means and the value it adds to specific healthcare pathways. Without a clear understanding of the proposed, defined use of a specified PRS test or assay its effective and responsible evaluation is not feasible.
Polygenic risk scores for CARDINAL study
CA Adebamao et al, Nature Genetics, May 5, 2022
(Posted: May-05-2022 2PM)
The Cardiometabolic Disorders in African-Ancestry Populations (CARDINAL) study site is a well-powered, first-of-its-kind resource for developing, refining and validating methods for research into polygenic risk scores that accounts for local ancestry, to improve risk prediction in diverse populations.
Improving polygenic prediction in ancestrally diverse populations
Y Ruan et al, Nature Genetics, May 5, 2022
(Posted: May-05-2022 2PM)
Polygenic risk scores (PRS) have attenuated cross-population predictive performance. As existing genome-wide association studies (GWAS) have been conducted predominantly in individuals of European descent, the limited transferability of PRS reduces their clinical value in non-European populations, and may exacerbate healthcare disparities. Recent efforts to level ancestry imbalance in genomic research have expanded the scale of non-European GWAS, although most remain underpowered. Here, we present a new PRS construction method, PRS-CSx, which improves cross-population polygenic prediction by integrating GWAS summary statistics from multiple populations.
Development of a clinical polygenic risk score assay and reporting workflow
L Hao et al, Nature Medicine, April 18, 2022
(Posted: Apr-18-2022 3PM)
Implementation of polygenic risk scores (PRS) may improve disease prevention and management but poses several challenges: the construction of clinically valid assays, interpretation for individual patients, and the development of clinical workflows and resources to support their use in patient care. Bridging two significant gaps between PRS development and clinical implementation, we developed a clinical genotyping array-based assay for six PRS and a process to report the results to patients and primary care physicians. The PRS were robust across multiple genotyping arrays and imputation pipelines. The distributions of unadjusted PRS varied by reported race in a large biobank, impeding clinical validation, but adjustment for population structure enabled the replication of published PRS–disease associations.
Leveraging fine-mapping and multipopulation training data to improve cross-population polygenic risk scores
O Weissbrod et al, Nature Genetics, April 7, 2022
(Posted: Apr-07-2022 2PM)
Polygenic risk scores suffer reduced accuracy in non-European populations, exacerbating health disparities. We propose PolyPred, a method that improves cross-population polygenic risk scores by combining two predictors: a new predictor that leverages functionally informed fine-mapping to estimate causal effects (instead of tagging effects), addressing linkage disequilibrium differences, and BOLT-LMM, a published predictor.
Perspectives of diverse Spanish- and English-speaking patients on the clinical use of polygenic risk scores
SA Sukiel et al, Genetics in Medicine, April 5, 2022
(Posted: Apr-06-2022 9AM)
Perceived utility of clinical PRS focused on the potential for personal health benefits, and most participants stated that high-risk results would prompt physician consultations and health behavior changes. There was little concern among participants about the limited predictive power of PRS for non-European populations. Barriers to uptake of PRS testing and adoption of PRS-related recommendations included socioeconomic factors, insurance status, race, ethnicity, language, and inadequate understanding of PRS.
New insights into the genetic etiology of Alzheimer’s disease and related dementias
C Bellenguez et al, Nature Genetics, April 4, 2022
(Posted: Apr-04-2022 1PM)
We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE e4 allele.
Polygenic scores in biomedical research
IJ Kullo et al, Nature Reviews Genetics, March 30, 2022
(Posted: Mar-30-2022 10AM)
Genome-wide association studies (GWAS) have implicated thousands of single-nucleotide polymorphisms (SNPs) in common complex diseases or traits. By calculating a weighted sum of the number of trait-associated alleles harboured by an individual, a polygenic score (PGS), also called a polygenic risk score (PRS), can be constructed that reflects an individual’s estimated genetic predisposition for a given phenotype. Here, 6 experts give their opinions on the utility of these probabilistic tools, their strengths and limitations, and the remaining barriers that need to be overcome for their equitable use.
How can we address the uncertainties regarding the potential clinical utility of polygenic score-based tests?
Moorthie Sowmiya et al. Personalized medicine 2022
(Posted: Mar-18-2022 10AM)
Polygenic scores have been developed as the mechanism by which knowledge of common variants can be used to investigate genetic contributions to disease risk. They serve as a biomarker to provide an estimate of the genetic liability for a particular disease. Discussion continues as to whether polygenic scores are a useful biomarker and their readiness for incorporation into clinical and public health practice. In this paper, we investigate the key challenges that need to be addressed, in the description and assessment of the clinical utility of polygenic score-based tests for use in clinical and public health practice.
Impact of polygenic risk communication: an observational mobile application-based coronary artery disease study
ED Muse et al, NPJ Digital Medicine, March 11, 2022
(Posted: Mar-12-2022 8AM)
We developed a smartphone application, MyGeneRank, to conduct a prospective observational cohort study involving the automated generation, communication, and electronic capture of response to a polygenic risk score (PRS) for coronary artery disease (CAD). We evaluated self-reported actions taken in response to personal CAD PRS information, with special interest in the initiation of lipid-lowering therapy. 19% (721/3,800) of participants provided complete responses for baseline and follow-up use of lipid-lowering therapy. 20% (n?=?19/95) of high CAD PRS vs 7.9% (n?=?8/101) of low CAD PRS participants initiated lipid-lowering therapy at follow-up (p-value?=?0.002).
Performance of polygenic risk scores for cancer prediction in a racially diverse academic biobank.
Wang Louise et al. Genetics in medicine : official journal of the American College of Medical Genetics 2021 12
(Posted: Mar-07-2022 9AM)
PRSs were derived from genome-wide significant single-nucleotide variations for 15 cancers in 20,079 individuals in an academic biobank. We evaluated the improvement in discriminatory accuracy by including cancer-specific PRS in patients of genetically-determined African and European ancestry. PRS moderately increased the ability to discriminate the cancer status in individuals of European but not African ancestry. Further large-scale studies are needed to identify ancestry-specific genetic factors in non-White populations to incorporate PRS into cancer risk assessment.
Interaction Testing and Polygenic Risk Scoring to Estimate the Association of Common Genetic Variants With Treatment Resistance in Schizophrenia.
Pardiñas Antonio F et al. JAMA psychiatry 2022 1 (3) 260-269
(Posted: Mar-03-2022 8AM)
Can common genetic variants be used to differentiate between treatment-resistant schizophrenia (TRS) and other forms of this disorder? Data from this genome-wide association study including 85?490 participants were used to estimate genome-wide single-nucleotide variation effect size differences between individuals with and without TRS, which were compatible with a polygenic model of treatment resistance. Results were used to generate a polygenic risk score, which was significantly associated with TRS status in independent incidence and prevalence samples.
Somatic mutational profiles and germline polygenic risk scores in human cancer.
Liu Yuxi et al. Genome medicine 2022 2 (1) 14
(Posted: Feb-16-2022 8AM)
We used polygenic risk scores (PRS) to summarize common germline variation associated with cancer risk and other cancer-related traits and examined the association between somatic mutational profiles and germline PRS in 12 cancer types from The Cancer Genome Atlas. Somatic mutational profiles were constructed from whole-exome sequencing data of primary tumors. Our analysis suggests that there are robust associations between tumor somatic mutational profiles and germline PRS. These may reflect the mechanisms through hormone regulation and immune responses that contribute to cancer etiology and drive cancer progression.
Capturing additional genetic risk from family history for improved polygenic risk prediction
T Lu et al, MEDRXIV, January 7, 2022
(Posted: Jan-08-2022 7AM)
Portability of 245 polygenic scores when derived from the UK Biobank and applied to 9 ancestry groups from the same cohort
F Prive et al, AJHG, January 6, 2022
(Posted: Jan-07-2022 6AM)
The low portability of polygenic scores (PGSs) across global populations is a major concern that must be addressed before PGSs can be used for everyone in the clinic. Indeed, prediction accuracy has been shown to decay as a function of the genetic distance between the training and test cohorts. However, such cohorts differ not only in their genetic distance but also in their geographical distance and their data collection and assaying, conflating multiple factors.
A tool for translating polygenic scores onto the absolute scale using summary statistics
O Pain et al, EJHG, January 4, 2022
(Posted: Jan-04-2022 6AM)
There is growing interest in the clinical application of polygenic scores as their predictive utility increases for a range of health-related phenotypes. However, providing polygenic score predictions on the absolute scale is an important step for their safe interpretation. We have developed a method to convert polygenic scores to the absolute scale for binary and normally distributed phenotypes. This method uses summary statistics, requiring only the area-under-the-ROC curve (AUC) or variance explained (R2) by the polygenic score, and the prevalence of binary phenotypes, or mean and standard deviation of normally distributed phenotype.
Large uncertainty in individual polygenic risk score estimation impacts PRS-based risk stratification
Y Ding et al, Nature Genetics, December 20, 2021
(Posted: Dec-21-2021 9AM)
Although the accuracy of polygenic risk scores (PRSs)—estimates of genetic value at the individual level—has been widely assessed, uncertainty in PRSs remains underexplored. In the present study, we show that Bayesian PRS methods can estimate the variance of an individual’s PRS and can yield well-calibrated credible intervals via posterior sampling. For 13 real traits in the UK Biobank (n?=?291,273), we observe large variances in individual PRS estimates which impact interpretation of PRS-based stratification; averaging across traits, only 0.8% (s.d.?=?1.6%) of individuals with PRS point estimates in the top decile have corresponding 95% credible intervals fully contained in the top decile.
The use of polygenic risk scores in pre-implantation genetic testing: an unproven, unethical practice
F Forzano et al, EJHG, December 17, 2021
(Posted: Dec-17-2021 6AM)
Polygenic risk scores for prediction of breast cancer risk in Asian populations
WK Ho et al, Genetics in Medicine, December 15, 2021
(Posted: Dec-17-2021 6AM)
Non-European populations are under-represented in genetics studies, hindering clinical implementation of breast cancer polygenic risk scores (PRSs). We developed PRSs using the largest available studies of Asian ancestry and to assess the transferability of PRS across ethnic subgroups.The development data set comprised 138,309 women from 17 case-control studies. PRSs were generated using a clumping and thresholding method, lasso penalized regression, an Empirical Bayes approach, a Bayesian polygenic prediction approach, or linear combinations of multiple PRSs. These PRSs were evaluated in 89,898 women from 3 prospective studies (1592 incident cases).
A polygenic risk score for multiple myeloma risk prediction.
Canzian Federico et al. European journal of human genetics : EJHG 2021 11
(Posted: Dec-03-2021 11AM)
Using 2361 MM cases and 1415 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium, we computed a weighted and an unweighted PRS. We observed associations with MM risk with OR?=?3.44, 95% CI 2.53–4.69, p?=?3.55?×?10-15 for the highest vs. lowest quintile of the weighted score, and OR?=?3.18, 95% CI 2.1?=?34–4.33, p?=?1.62?×?10-13 for the highest vs. lowest quintile of the unweighted score. We found a convincing association of a PRS generated with 23 SNPs and risk of MM.
Applications of Polygenic Risk Scores to Population Health: Where Are We?
Khoury MJ et al, CDC Blog Post, November 29, 2021
(Posted: Nov-30-2021 9AM)
An international multidisciplinary group of experts in genetics, law, ethics, behavioral sciences, and other fields reviews the state of science on polygenic scores and highlights risks and gaps before widespread use in practice. The rapid developments in the field of PRS is encouraging. As more evidence is accumulated, one should be constantly reminded that the evidentiary foundation for any genetic test, including PRS, should be limited to its intended use. The CDC ACCE framework (analytic validity, clinical validity, clinical utility and ethical, legal and social implications) can be applied to the evaluation of PRS in clinical practice.
Clinical utility of polygenic risk scores for coronary artery disease.
Klarin Derek et al. Nature reviews. Cardiology 2021 11
(Posted: Nov-28-2021 10AM)
In this Review, we describe technical and downstream considerations for the derivation and validation of polygenic risk scores and current evidence for their efficacy and safety. We discuss the implementation of these scores in clinical medicine for uses including risk prediction and screening algorithms for coronary artery disease, prioritization of patient subgroups that are likely to derive benefit from treatment, and efficient prospective clinical trial designs.
Responsible use of polygenic risk scores in the clinic: potential benefits, risks and gaps
Polygenic Risk Score Task Force of the International Common Disease Alliance, Nature Medicine, November 15, 2021
(Posted: Nov-16-2021 8AM)
The potential benefits of PRSs include cost-effective enhancement of primary disease prevention, more refined diagnoses and improved precision when prescribing medicines. However, these must be weighed against the potential risks, such as uncertainties and biases in PRS performance, as well as potential misunderstanding and misuse of these within medical practice and in wider society. By addressing key issues including gaps in best practices, risk communication and regulatory frameworks, PRSs can be used responsibly to improve human health.
Genome-wide association analyses highlight etiological differences underlying newly defined subtypes of diabetes
DM Aly et al, Nature Genetics, November 4, 2021
(Posted: Nov-05-2021 6PM)
We used genome-wide association and genetic risk score (GRS) analysis to compare the underlying genetic drivers. Individuals from the Swedish ANDIS (All New Diabetics In Scania) study were compared to individuals without diabetes; the Finnish DIREVA (Diabetes register in Vasa) and Botnia studies were used for replication. We show that subtypes differ with regard to family history of diabetes and association with GRS for diabetes-related traits.
Polygenic risk for breast cancer: in search for potential clinical utility
T Wang et al, Int J Epi, October 31, 2021
(Posted: Oct-31-2021 8PM)
The use of a polygenic risk score (PRS) as an independent risk factor for common diseases is becoming mainstream. The initial hype on their clinical applicability appears to be maturing into appraisals of their characteristics in relation to traditional risk assessment schemes, the particular statistical modelling characteristics that would be necessary for their global use in various populations7 and their potential added public health value
Prognostic value of polygenic risk scores for adults with psychosis
I Landi et al, Nature Medicine, September 6, 2021
(Posted: Sep-07-2021 6AM)
We analyzed clinical and genetic data from two multi-ethnic cohorts totaling 8,541 adults with SCZ and related psychotic disorders, to assess whether the SCZ PRS improves the prediction of poor outcomes relative to clinical features captured in a standard psychiatric interview. For all outcomes investigated, the SCZ PRS did not improve the performance of predictive models, an observation that was generally robust to divergent case ascertainment strategies and the ancestral background of the study participants.
NIH awards $38 million to improve utility of polygenic risk scores in diverse populations
P Ganguly, NHGRI, August 16, 2021
(Posted: Aug-17-2021 2PM)
The new consortium will pool genomic information from existing and new datasets to develop and evaluate the methods used for calculating polygenic risk scores for specific diseases, with an emphasis on studying people from different ancestries. Researchers will also identify best practices to ensure that the scores accurately predict disease across diverse populations.
Polygenic Risk Scores for Breast Cancer—Can They Deliver on the Promise of Precision Medicine?
PD Shah, JAMA Network Open, August 4, 2021
(Posted: Aug-04-2021 0PM)
Currently, guidelines advise against the clinical use of PRSs due to limitations in interpretation and encourage further research. Essential objectives of this research must be to examine if, when, and in whom PRSs are useful. Studies will need to not only consider discriminatory capacity, equity, and clinical utility, but also psychosocial impact and cost-effectiveness, each in context. Polygenic risk scores may well personalize cancer risk management and improve patient outcomes, but we will need to further investigate these critical issues before determining whether they can fully deliver.
Generalizability of Polygenic Risk Scores for Breast Cancer Among Women With European, African, and Latinx Ancestry
C Liu et al, JAMA Network Open, August 4, 2021
(Posted: Aug-04-2021 11AM)
In this multicenter cohort study linking electronic medical records to genotyping data that including 39?591 women, PRSs were significantly associated with breast cancer risk in women of all ancestries, although the effect sizes were smaller in women with African ancestry.
Breast cancer polygenic risk scores: a 12-month prospective study of patient reported outcomes and risk management behavior
T Yanes et al, GIM, August 2, 2021
(Posted: Aug-02-2021 4PM)
Of the 208 participants, 165 (79%) received their PRS. Among receivers, there were no changes in anxiety or distress following testing. However, compared to women with a low PRS, those with a high PRS reported greater genetic testing–specific distress, perceived risk, decisional regret, and less genetic testing–positive response. At 12 months, breast screening and uptake of risk-reducing strategies were consistent with current guidelines of breast cancer risk management.
Identifying individuals with high risk of Alzheimer’s disease using polygenic risk scores
G leonenko et al, Nat Comms, July 2021
(Posted: Jul-26-2021 11AM)
Polygenic Risk Scores (PRS) for AD offer unique possibilities for reliable identification of individuals at high and low risk of AD. However, there is little agreement in the field as to what approach should be used for genetic risk score calculations, how to model the effect of APOE, what the optimal p-value threshold (pT) for SNP selection is and how to compare scores between studies and methods. We show that the best prediction accuracy is achieved with a model with two predictors (APOE and PRS excluding APOE region).
Contextualizing genetic risk score for disease screening and rare variant discovery
D Zhou et al, Nature Comms, July 20, 2021
(Posted: Jul-21-2021 7AM)
Studies of the genetic basis of complex traits have demonstrated a substantial role for common, small-effect variant polygenic burden (PB) as well as large-effect variants (LEV, primarily rare). We identify sufficient conditions in which GWAS-derived PB may be used for well-powered rare pathogenic variant discovery or as a sample prioritization tool for whole-genome or exome sequencing.
Why do people seek out polygenic risk scores for complex disorders, and how do they understand and react to results?
L Peck et al, EJHG, July 18, 2021
(Posted: Jul-20-2021 7AM)
We sought to explore individuals’ motivations for using their direct-to-consumer genetic testing data to generate polygenic risk scores (PRSs) using a not-for-profit third-party tool, and to assess understanding of, and reaction to their results. Using a cross-sectional design, users of Impute.me who had already accessed PRS results were invited to complete an online questionnaire asking about demographics, motivations for seeking PRSs, understanding and interpretation of PRSs.
Potential of polygenic risk scores for improving population estimates of women's breast cancer genetic risks.
Wolfson Michael et al. Genetics in medicine : official journal of the American College of Medical Genetics 2021 7
(Posted: Jul-08-2021 8AM)
The Canadian heritable breast cancer risk distribution was estimated using a novel genetic mixing model (GMM). A realistically representative sample of women was synthesized based on empirically observed demographic patterns for appropriately correlated family history. Generally, the PRS was most predictive for identifying women at high risk, while family history was the weakest. Only the PRS identified any women at low risk of breast cancer.
Problems with Using Polygenic Scores to Select Embryos.
Turley Patrick et al. The New England journal of medicine 2021 7 (1) 78-86
(Posted: Jul-04-2021 9AM)
Companies have recently begun to sell a new service to patients considering in vitro fertilization: embryo selection based on polygenic scores (ESPS). These scores represent individualized predictions of health and other outcomes derived from genomewide association studies in adults to partially predict these outcomes. This article includes a discussion of many factors that lower the predictive power of polygenic scores in the context of embryo selection and quantifies these effects for a variety of clinical and nonclinical traits.
Resource profile and user guide of the Polygenic Index Repository
J Becker et al, Nature Human Behavior, June 17, 2021
(Posted: Jun-18-2021 6AM)
Polygenic indexes (PGIs) are DNA-based predictors. Their value for research in many scientific disciplines is growing rapidly. As a resource for researchers, we used a consistent methodology to construct PGIs for 47 phenotypes in 11 datasets. To maximize the PGIs’ prediction accuracies, we constructed them using genome-wide association studies—some not previously published—from multiple data sources.
What Are Polygenic Risk Scores?
CDC, June 2021
(Posted: Jun-16-2021 8AM)
Polygenic risk scores can provide a measure of your disease risk due to your genes. Combining polygenic risk scores with other factors that affect disease risk can give a better idea of how likely you are to get a specific disease than considering either alone. Knowing how likely you are to get a disease can help you take steps to prevent it or find it earlier, when it is easier to treat.
The predictive ability of the 313 variant–based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant
IMM Lakeman et al, Genetics in Medicine, June 10, 2021
(Posted: Jun-11-2021 8AM)
Will polygenic risk scores for cancer ever be clinically useful?
A Sud et al, NPJ Precision Oncology, May 21, 2021
(Posted: May-22-2021 0PM)
The clinical utility of identification of high-impact mutations in genes such as BRCA1 and MLH1 is not under dispute: such mutations provide effective risk discrimination and there are established clinical pathways for those in whom mutations are identified. However, the notion that PRSs will offer equivalent utility population-wide by providing informative risk stratification across multiple diseases is misleading. Raising unrealistic expectations and implementing programs without careful evaluation risks compromising the application of PRSs for specific niches, and indeed, of genomic medicine.
Response to Polygenic Risk: Results of the MyGeneRank Mobile Application-Based Coronary Artery Disease Study
ED Muse et al, MEDRXIV, April 28, 2021
(Posted: Apr-29-2021 7AM)
We evaluated self-reported actions taken in response to personal CAD PRS information, with special interest in the initiation of lipid lowering therapy. 20% of high genetic risk (n=95) vs 7.9% of low genetic risk individuals (n=101) initiated lipid lowering therapy at follow-up (p-value = 0.002). The initiation of both statin and non-statin lipid lowering therapy was associated with degree of genetic risk.
Extension of Mendelian Randomization to Identify Earliest Manifestations of Alzheimer's Disease: Genetic Risk Score for Alzheimer's Disease Reduces BMI by Age 50.
Brenowitz Willa D et al. American journal of epidemiology 2021 4
(Posted: Apr-18-2021 8AM)
Weight loss or lower Body Mass Index (BMI) may be an early symptom of Alzheimer's disease (AD) but when this begins to emerge is difficult to estimate with traditional observational data. In an extension of Mendelian randomization, we used genetic risk for late-onset AD risk to estimate the causal effect of AD on BMI and the earliest ages at which AD-related weight loss (or lower BMI as a proxy) occurs. 407,386 UK Biobank participants enrolled 2007-2010 without dementia.
Evaluating Polygenic Risk Scores for Breast Cancer in Women of African Ancestry.
Du Zhaohui et al. Journal of the National Cancer Institute 2021 3
(Posted: Mar-28-2021 7AM)
We assembled genotype data for women of African ancestry, including 9,241 cases and 10,193 controls. We evaluated associations of 179- and 313-variant PRSs with overall and subtype-specific BC risk. The PRSs stratify BC risk in women of African ancestry, with attenuated performance compared to that reported in European, Asian and Latina populations. Future work is needed to improve BC risk stratification for women of African ancestry.
Do Breast Cancer Risk Scores Work for You?
Houlahan Kathleen E et al. Journal of the National Cancer Institute 2021 3
(Posted: Mar-28-2021 7AM)
In theory, predicting risk from PRS is a minimally invasive strategy for prioritizing high risk individuals towards early screening and intervention. In practice, the actualization of PRS is currently limited and heavily biased towards one population: individuals of European descent.
Prospective evaluation of a breast-cancer risk model integrating classical risk factors and polygenic risk in 15 cohorts from six countries.
Hurson Amber N et al. International journal of epidemiology 2021 3
(Posted: Mar-28-2021 7AM)
Fifteen prospective cohorts from six countries with 239?340 women (7646 incident breast-cancer cases) of European ancestry aged 19–75?years were included. Integrating a 313-variant PRS with classical risk factors can improve the identification of European-ancestry women at elevated risk who could benefit from targeted risk-reducing strategies under current clinical guidelines.
NIH researchers develop guidelines for reporting polygenic risk scores
P Ganguly, NHGRI, March 10, 20201
(Posted: Mar-12-2021 7AM)
A real challenge is that the research community has not adopted any universal best practices for reporting polygenic risk scores. With the field growing as fast as it is, we need standards in place so we can meaningfully evaluate these scores and determine which ones are ready to be used in clinical care.
Improving reporting standards for polygenic scores in risk prediction studies
H Wand et al, Nature, March 10, 2021
(Posted: Mar-11-2021 7AM)
We present the Polygenic Risk Score Reporting Standards (PRS-RS), in which we update the Genetic Risk Prediction Studies (GRIPS) Statement to reflect the present state of the field. Drawing on the input of experts in epidemiology, statistics, disease-specific applications, implementation and policy, this comprehensive reporting framework defines the minimal information that is needed to interpret and evaluate PRSs, especially with respect to downstream clinical applications.
The Polygenic Score Catalog as an open database for reproducibility and systematic evaluation
SA Lambert et al, Nature Genetics, March 10, 2021
(Posted: Mar-11-2021 7AM)
We present the Polygenic Score (PGS) Catalog, an open resource of published scores (including variants, alleles and weights) and consistently curated metadata required for reproducibility and independent applications. The PGS Catalog has capabilities for user deposition, expert curation and programmatic access, thus providing the community with a platform for PGS dissemination, research and translation.
Validation of an Integrated Risk Tool, Including Polygenic Risk Score, for Atherosclerotic Cardiovascular Disease in Multiple Ethnicities and Ancestries.
Weale Michael E et al. The American journal of cardiology 2021
(Posted: Mar-09-2021 9AM)
The American College of Cardiology / American Heart Association pooled cohort equations tool (ASCVD-PCE) is currently recommended to assess 10-year risk for atherosclerotic cardiovascular disease (ASCVD). ASCVD-PCE does not currently include genetic risk factors. Polygenic risk scores (PRSs) have been shown to offer a powerful new approach to measuring genetic risk for common diseases, including ASCVD, and to enhance risk prediction when combined with ASCVD-PCE.
The need for polygenic score reporting standards in evidence-based practice: lipid genetics use case.
Wand Hannah et al. Current opinion in lipidology 2021 Feb
(Posted: Feb-09-2021 10AM)
Polygenic scores (PGS) are used to quantify the genetic predisposition for heritable traits, with hypothesized utility for personalized risk assessments. Lipid PGS are primed for clinical translation, but evidence-based practice changes will require rigorous PGS standards to ensure reproducibility and generalizability.
Polygenic risk modeling with latent trait-related genetic components
M Aguirre et al, EJHG, February 8, 2021
(Posted: Feb-09-2021 8AM)
Highly elevated polygenic risk scores are better predictors of myocardial infarction risk early in life than later
M Isgut et al, Genome Medicine, January 28, 2021
(Posted: Jan-29-2021 7AM)
Polygenic risk scores improve cardiovascular risk stratification early in life when knowledge of later-life risk factors is unavailable. However, by middle age, when many risk factors are known, the improvement attributed to PRS is marginal for the general population.
Polygenic risk scores in the clinic: new perspectives needed on familiar ethical issues
ACF Lewis et al, Genome Medicine, January 28 2021
(Posted: Jan-29-2021 7AM)
Reducing health disparities is a key value for public health, but clinical use of polygenic risk scores could exacerbate race-based health disparities. In this commentary, the authors argue that despite the parallels to the monogenic setting, new work is urgently needed to gather data, consider normative implications, and develop best practices around this emerging branch of genomics.
Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity.
Harper Andrew R et al. Nature genetics 2021 Jan
(Posted: Jan-27-2021 9AM)
A genome-wide association study of 2,780 cases and 47,486 controls identified 12 genome-wide-significant susceptibility loci for HCM. Single-nucleotide polymorphism heritability indicated a strong polygenic influence, especially for sarcomere-negative HCM. A genetic risk score showed substantial influence on the odds of HCM in a validation study, halving the odds in the lowest quintile and doubling them in the highest quintile, and also influenced phenotypic severity.
Polygenic risk scores in cardiovascular risk prediction: A cohort study and modelling analyses.
Sun Luanluan et al. PLoS medicine 2021 Jan (1) e1003498
(Posted: Jan-18-2021 8AM)
We quantified the incremental predictive gain with polygenic risk scores on top of conventional risk factors using data on 306,654 individuals from UK Biobank.?Addition of PRSs to conventional risk factors provided modest improvement in prediction of first-onset CVD. even moderate improvements could translate into meaningful clinical benefit if applied at scale, and lead to the prevention of 7% more CVD events than conventional risk factors alone.
Risk of Early-Onset Depression Associated With Polygenic Liability, Parental Psychiatric History, and Socioeconomic Status.
Agerbo Esben et al. JAMA psychiatry 2021 Jan
(Posted: Jan-14-2021 9AM)
In this case-cohort study of 17?098 patients with depression, the absolute risk of depression by the age of 30 years differed substantially depending on an individual’s combination of risk factors, ranging from 1.0% among male individuals with high socioeconomic status in the bottom 2% of the polygenic risk score distribution to 23.7% among female individuals in the top 2% of PRS with a parental history of psychiatric disorders.
Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction.
Conti David V et al. Nature genetics 2021 Jan
(Posted: Jan-06-2021 8AM)
We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 for men of European ancestry to 3.74 for men of African ancestry.
Sexual Differences in Genetic Predisposition of Coronary Artery Disease
Y Huang et al, Circ Genetics Precision Med, December 2020
(Posted: Dec-18-2020 8AM)
Using data from the UK Biobank, we found that the associations of genetic risk scores were stronger among men than women. Using a score of 161 loci, we observed a 2.4 times higher risk for incident CAD comparing men with high genetic risk to men with low genetic risk, but an 80 percent greater risk comparing women with high genetic risk to women with low genetic risk.
Individuals with common diseases but with a low polygenic risk score could be prioritized for rare variant screening.
Lu Tianyuan et al. Genetics in medicine : official journal of the American College of Medical Genetics 2020 Oct
(Posted: Oct-29-2020 11AM)
Identifying rare genetic causes of common diseases can improve diagnostic and treatment strategies, but incurs high costs. We tested whether individuals with common disease and low polygenic risk score (PRS) for that disease generated from less expensive genome-wide genotyping data are more likely to carry rare pathogenic variants.
Mendelian randomization study of maternal influences on birthweight and future cardiometabolic risk in the HUNT cohort
GH Moen et al, Nature Comms, October 25, 2020
(Posted: Oct-27-2020 0PM)
We explore if a genetic risk score (GRS) of maternal SNPs associated with offspring birthweight is also associated with offspring cardiometabolic risk factors, after controlling for offspring GRS, in up to 26,057 mother–offspring pairs. Our results suggest that the maternal intrauterine environment, as proxied by maternal SNPs that influence offspring birthweight, is unlikely to be a major determinant of adverse cardiometabolic outcomes.
From Basic Science to Clinical Application of Polygenic Risk Scores: A Primer.
Wray Naomi R et al. JAMA psychiatry 2020 Sep
(Posted: Oct-01-2020 9AM)
Utility of polygenic risk scores in clinical medicine and ethical issues related to their use should be evaluated in the context of realistic expectations of what PRS can and cannot deliver. For different diseases, PRS could have utility in community settings or could contribute to clinical decision-making for those presenting with symptoms but where formal diagnosis is unclear. More data are needed to allow development of PRS in practice.
Polygenic architecture informs potential vulnerability to drug-induced liver injury
M Koido et al, Nature Medicine, September 7, 2020
(Posted: Sep-08-2020 8AM)
Drug-induced liver injury (DILI) is a leading cause of termination in drug development. We developed a polygenic risk score (PRS) for DILI by aggregating effects of numerous genome-wide loci identified from previous large-scale genome-wide association studies. The PRS predicted the susceptibility to DILI for fasiglifam, amoxicillin–clavulanate or flucloxacillin
