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325 hot topic(s) found with the query "Genetic risk score"

Utility of polygenic scores across diverse diseases in a hospital cohort for predictive modeling
TH Sun et al, Nature Comm, April 12, 2024 (Posted: Apr 12, 2024 9AM)

From the abstract: "Polygenic scores estimate genetic susceptibility to diseases. We systematically calculated polygenic scores across 457 phenotypes using genotyping array data from Medical University Hospital. Logistic regression models assessed polygenic scores’ ability to predict disease traits. The polygenic score model with the highest accuracy, based on maximal area under the receiver operating characteristic curve (AUC), is provided on the GeneAnaBase website of the hospital. Our findings indicate 49 phenotypes with AUC greater than 0.6, predominantly linked to endocrine and metabolic diseases. "

Future implications of polygenic risk scores for life insurance underwriting.
Tatiane Yanes et al. NPJ Genom Med 2024 3 (1) 25 (Posted: Apr 01, 2024 9AM)

From the abstract: "As PGS is increasingly utilized in research and clinical practice, it is pivotal that careful consideration is given to the potential insurance implications of PGS to ensure consumer protection against GD. For the full potential benefits of PGS to be realized, and its clinical utility determined across various use cases, individuals will need to be confident that they can participate in research studies and access clinical genetic testing without fear of insurance discrimination. Clarification is needed regarding the extent to which existing protections and legislation relating to monogenic testing may also extend to PGS test results. "

Researchers optimize genetic tests for diverse populations to tackle health disparities
NIH, February 2024 Brand (Posted: Mar 01, 2024 0PM)

From the website: " To prevent an emerging genomic technology from contributing to health disparities, a scientific team funded by the National Institutes of Health has devised new ways to improve a genetic testing method called a polygenic risk score. Since polygenic risk scores have not been effective for all populations, the researchers recalibrated these genetic tests using ancestrally diverse genomic data. As reported in Nature Medicine, the optimized tests provide a more accurate assessment of disease risk across diverse populations."

Novel Polygenic Risk Score and Established Clinical Risk Factors for Risk Estimation of Aortic Stenosis.
Aeron M Small et al. JAMA Cardiol 2024 2 (Posted: Feb 29, 2024 8AM)

From the abstract: " How does genetic risk compare to clinical risk factors in estimating aortic stenosis? In this cohort study of individuals from the Million Veteran Program and the Thrombolysis in Myocardial Infarction (TIMI) trials, a novel aortic stenosis polygenic risk score (PRS) performed comparably to most clinical risk factors in risk estimation of aortic stenosis. However, the addition of an aortic stenosis PRS to clinical risk factors had only incremental improvement in risk estimation. The findings suggest that the development of an aortic stenosis polygenic risk score is possible; however, further work is warranted to translate such a score into clinical practice. "

Recent advances in polygenic scores: translation, equitability, methods and FAIR tools.
Ruidong Xiang et al. Genome Med 2024 2 (1) 33 (Posted: Feb 22, 2024 11AM)

From the abstract: " We review the latest potential benefits of PGS in the clinic and challenges to implementation. PGS could augment risk stratification through combined use with traditional risk factors (demographics, disease-specific risk factors, family history, etc.), to support diagnostic pathways, to predict groups with therapeutic benefits, and to increase the efficiency of clinical trials. However, there exist challenges to maximizing the clinical utility of PGS, including FAIR (Findable, Accessible, Interoperable, and Reusable) use and standardized sharing of the genomic data needed to develop and recalculate PGS, the equitable performance of PGS across populations."

Selection, optimization and validation of ten chronic disease polygenic risk scores for clinical implementation in diverse US populations
NJ Lennon et al, Nature Medicine, February 19, 2024 (Posted: Feb 20, 2024 7AM)

From the abstract: " From an initial list of 23 conditions, ten were selected for implementation based on PRS performance, medical actionability and potential clinical utility, including cardiometabolic diseases and cancer. Standardized metrics were considered in the selection process, with additional consideration given to strength of evidence in African and Hispanic populations. We then developed a pipeline for clinical PRS implementation (score transfer to a clinical laboratory, validation and verification of score performance), and used genetic ancestry to calibrate PRS mean and variance, utilizing genetically diverse data from 13,475 participants of the All of Us Research Program cohort to train and test model parameters. "

Polygenic Risk in Families With Spontaneous Coronary Artery Dissection.
Ingrid Tarr et al. JAMA Cardiol 2024 1 (Posted: Jan 25, 2024 7AM)

From the abstract: "In this genetic association study including 13 families with SCAD, 173 individuals with sporadic SCAD, and 1127 controls, a polygenic risk score for SCAD was associated with significantly higher odds of disease in both familial and sporadic SCAD compared with healthy controls. We conclude that common genetic variants play an important role in all forms of SCAD, can potentially explain familial clustering, and further emphasize the complex genetic etiology of disease. "

Validity of European-centric cardiometabolic polygenic scores in multi-ancestry populations
CC Topricneau et al, EJHG, January 5, 2024 (Posted: Jan 08, 2024 8AM)

From the abstract: "Polygenic scores (PGSs) provide an individual level estimate of genetic risk for any given disease. Since most PGSs have been derived from genome wide association studies (GWASs) conducted in populations of White European ancestry, their validity in other ancestry groups remains unconfirmed. This is especially relevant for cardiometabolic diseases which are known to disproportionately affect people of non-European ancestry. "

Polygenic Risk Prediction in Diverse Populations and Contexts: Scientific and Ethical Considerations
ELSI Forum Webinar, January 12, 2024 (Posted: Dec 20, 2023 9AM)

From the website: "The differential performance of polygenic risk scores (PRS) by population genetic background is a well-known scientific concern and one of the most important barriers to their equitable translation for clinical use. Not only must the social repercussions of how people are grouped for test development be considered, but the communication of their context specificity and differential performance to patients and their clinicians must be carefully managed. Drawing on recent research experiences with the development, validation, and implementation of PRS for common complex disease risk, this webinar will explore the scientific and ethical considerations relevant to the widespread adoption of PRS for clinical care."

Pragmatic Approach to Applying Polygenic Risk Scores to Diverse Populations.
Aniruddh P Patel et al. Curr Protoc 2023 11 (11) e911 (Posted: Nov 07, 2023 0PM)

From the abstract: " We present a pragmatic approach to optimize a PRS for a population of interest that leverages publicly available data and methods and consists of seven steps that are easily implemented without the requirement of expertise in complex genetics: step 1, selecting source genome-wide association studies (GWAS) and imputation; step 2, selecting methods to compute polygenic score; step 3, adjusting scores using principal components of genetic ancestry; step 4, selecting the best performing score; step 5, defining percentiles of a population distribution; step 6, validating performance of the optimized polygenic score; and step 7, implementing the optimized polygenic score in clinical practice."

Ancestry-specific polygenic risk scores are risk enhancers for clinical cardiovascular disease assessments.
George B Busby et al. Nat Commun 2023 11 (1) 7105 (Posted: Nov 06, 2023 10AM)

From the abstract: " We develop and validate ancestry-specific Polygenic Risk Scores (PRSs) for Coronary Artery Disease (CAD) using 29,389 individuals from diverse cohorts and genetic ancestry groups. The CAD PRSs outperform published scores with an average Odds Ratio per Standard Deviation of 1.57 (SD = 0.14) and identify between 12% and 24% of individuals with high genetic risk. Using this risk factor to reclassify borderline or intermediate 10 year Atherosclerotic Cardiovascular Disease (ASCVD) risk improves assessments for both CAD (Net Reclassification Improvement (NRI) = 13.14% (95% CI 9.23–17.06%)) and ASCVD (NRI = 10.70 (95% CI 7.35-14.05)) in an independent cohort of 9,691 individuals. "

Power of inclusion: Enhancing polygenic prediction with admixed individuals.
Yosuke Tanigawa et al. Am J Hum Genet 2023 10 (Posted: Oct 30, 2023 8AM)

From the abstract: "Admixed individuals offer unique opportunities for addressing limited transferability in polygenic scores (PGSs), given the substantial trans-ancestry genetic correlation in many complex traits. However, they are rarely considered in PGS training, given the challenges in representing ancestry-matched linkage-disequilibrium reference panels for admixed individuals. Here we present inclusive PGS (iPGS), which captures ancestry-shared genetic effects by finding the exact solution for penalized regression on individual-level data. "

Polygenic risk scores for disease risk prediction in Africa: current challenges and future directions
S Fatumo et al, Genome Medicine, October 30, 2023 (Posted: Oct 30, 2023 8AM)

From the abstract: " Polygenic risk scores (PRS), which combine multiple contributing variants to predict disease risk, have the potential to influence the implementation for precision medicine. However, the majority of existing PRS were developed from European data with limited transferability to African populations. We (1) discuss the factors contributing to the poor transferability of PRS in African populations, (2) showcase the novel Africa genomic datasets for PRS development, (3) explore the potential clinical utility of PRS in African populations, and (4) provide insight into the future of PRS in Africa."

From a Fledgling Genetic Science, A Murky Market for Prediction
A Smart, Undark, October 27, 2023 (Posted: Oct 27, 2023 4PM)

From the article: "Although polygenic scores alone may not be powerful predictors of disease, many researchers are optimistic that they can be combined with other, more conventional methods of risk estimation to improve screening for common conditions like cancer, cardiovascular diseases, and diabetes. At the same time, however, a chorus of experts say that society should temper any expectations that polygenic scores will revolutionize health care. "

Are we nearly there yet? Starts and stops on the road to use of polygenic scores.
Sowmiya Moorthie et al. J Community Genet 2023 9 (Posted: Sep 28, 2023 11AM)

From the paper: "The articles in this collection examine the practical, social, and ethical implications of polygenic risk scores across healthcare settings and different populations. As illustrated by the articles in this collection, uncertainty remains regarding the transferability, utility, and validity of PGS and how to responsibly adopt and implement this technology."

A linear weighted combination of polygenic scores for a broad range of traits improves prediction of coronary heart disease.
Kristjan Norland et al. Eur J Hum Genet 2023 9 (Posted: Sep 27, 2023 8AM)

From the abstract: "Polygenic scores (PGS) for coronary heart disease (CHD) are constructed using GWAS summary statistics for CHD. However, pleiotropy is pervasive in biology and disease-associated variants often share etiologic pathways with multiple traits. Therefore, incorporating GWAS summary statistics of additional traits could improve the performance of PGS for CHD. "

Boosting the power of genome-wide association studies within and across ancestries by using polygenic scores.
Adrian I Campos et al. Nat Genet 2023 9 (Posted: Sep 20, 2023 7AM)

From the abstract: "Genome-wide association studies (GWASs) have been mostly conducted in populations of European ancestry, which currently limits the transferability of their findings to other populations. Here, we show, through theory, simulations and applications to real data, that adjustment of GWAS analyses for polygenic scores (PGSs) increases the statistical power for discovery across all ancestries. "

Principles and methods for transferring polygenic risk scores across global populations
L Kachuri et al, Nature Rev Genetics, August 24, 2023 (Posted: Aug 24, 2023 10AM)

From the abstract: "Polygenic risk scores (PRSs) summarize the genetic predisposition of a complex human trait or disease and may become a valuable tool for advancing precision medicine. However, PRSs that are developed in populations of predominantly European genetic ancestries can increase health disparities due to poor predictive performance in individuals of diverse and complex genetic ancestries. We describe genetic and modifiable risk factors that limit the transferability of PRSs across populations and review the strengths and weaknesses of existing PRS construction methods for diverse ancestries."

Genotype error due to low-coverage sequencing induces uncertainty in polygenic scoring
E Petter et al, AJHG, July 24, 2023 (Posted: Jul 25, 2023 8AM)

Polygenic scores (PGSs) have emerged as a standard approach to predict phenotypes from genotype data in a wide array of applications from socio-genomics to personalized medicine. Traditional PGSs assume genotype data to be error-free, ignoring possible errors and uncertainties introduced from genotyping, sequencing, and/or imputation. In this work, we investigate the effects of genotyping error due to low coverage sequencing on PGS estimation.

Improving polygenic score prediction for coronary artery disease across populations of diverse ancestry
Nature Medicine, July 10, 2023 (Posted: Jul 10, 2023 11AM)

Genome-wide polygenic scores quantify inherited risk by integrating information from many common DNA variants and hold considerable promise for enabling personalized medicine. By integrating information on coronary artery disease (CAD) and CAD-related risk traits from genetic datasets that were larger and more diverse than those used in the past, we developed an improved multi-ancestry polygenic predictor for CAD.

Contemporary Polygenic Scores of Low-Density Lipoprotein Cholesterol and Coronary Artery Disease Predict Coronary Atherosclerosis in Adolescents and Young Adults.
Rodrigo Guarischi-Sousa et al. Circ Genom Precis Med 2023 7 e004047 (Posted: Jul 10, 2023 8AM)

A multi-ancestry polygenic risk score improves risk prediction for coronary artery disease.
Aniruddh P Patel et al. Nat Med 2023 7 (Posted: Jul 07, 2023 9AM)

Identification of individuals at highest risk of coronary artery disease (CAD)—ideally before onset—remains an important public health need. Prior studies have developed genome-wide polygenic scores to enable risk stratification, reflecting the substantial inherited component to CAD risk. Here we develop a new and significantly improved polygenic score for CAD, termed GPSMult, that incorporates genome-wide association data across five ancestries for CAD (>269,000 cases and >1,178,000 controls) and ten CAD risk factors.

The role of polygenic risk scores in breast cancer risk perception and decision-making.
Leslie Riddle et al. J Community Genet 2023 6 (Posted: Jun 20, 2023 7AM)

Polygenic risk scores (PRS) have the potential to improve the accuracy of clinical risk assessments, yet questions about their clinical validity and readiness for clinical implementation persist. Understanding how individuals integrate and act on the information provided by PRS is critical for their effective integration into routine clinical care, yet few studies have examined how individuals respond to the receipt of polygenic risk information.

To Prevent Heart Attacks, Doctors Try a New Genetic Test
G Kolata, NY Times, May 30, 2023 (Posted: Jun 02, 2023 9AM)

A new genetic test, known as a polygenic risk score looks at a collection of thousands of genetic variants. Each variant contributes little on its own to heart disease risk, but the variants together might point to those who are likely to have heart attacks. Cardiologists hope to use such tests which are not typically covered by health insurance, to identify people most likely to have heart attacks long before they have them.

Development and Validation of the Vanderbilt PRS-KS, an Instrument to Quantify Polygenic Risk Score Knowledge
D Stubbs et al, GIM Open, May 31, 2023 (Posted: Jun 01, 2023 6AM)

As polygenic risk scores (PRS) enter clinical practice, healthcare providers' and the publics’ comprehension of PRS results are of great importance, yet poorly understood. We present the Vanderbilt Polygenic Risk Scores Knowledge Score (Vanderbilt PRS-KS), a tool to quantify PRS knowledge. The tool was developed by a team of genetic counselors and physicians to cover key conceptual facts pertaining to PRSs. We recruited (n=500) individuals with demographics representative of a U.S. sample and graduate-level healthcare students (n=74) at a large academic medical center to participate in this validation study.

Education and Electronic Medical Records and Genomics Network, Challenges and Lessons Learned from a Large-Scale Clinical Trial Using Polygenic Risk Scores
JJ Connolly et al, Genet Med, May 26, 2023 (Posted: May 27, 2023 6AM)

The electronic Medical Records and Genomics (eMERGE) Network is conducting a collaborative study which will return PRS to 25,000 pediatric and adult participants. All participants will receive a risk report, potentially classifying them as high risk (~2-10% per condition) for one or more of 10 conditions based on PRS. The study population is enriched by participants from racial and ethnic minority populations, underserved populations, and populations who experience poorer medical outcomes.

Coronary Artery Calcium Score and Polygenic Risk Score for the Prediction of Coronary Heart Disease Events
SS Khan et al, JAMA Network Open, May 23, 2023 (Posted: May 23, 2023 2PM)

Does discrimination change when either a coronary artery calcium score or a polygenic risk score is added to a coronary heart disease (CHD) prediction model based on traditional risk factors? In 2 population-based studies involving 3208 adults aged 45 years through 79 years (Multi-Ethnic Study of Atherosclerosis [MESA], median age 61 years and the Rotterdam Study [RS], median age, 67 years) and of European ancestry, a coronary artery calcium score significantly improved discrimination when added to a traditional risk factor–based score (MESA, 0.09; Rotterdam Study, 0.06), but the polygenic risk score did not. Similar findings were observed when stratified by median age.

Utility of polygenic risk scores in UK cancer screening: a modelling analysis
C Huntley et al, Lancet Oncology, May 2023 (Posted: May 12, 2023 6AM)

It is proposed that, through restriction to individuals delineated as high risk, polygenic risk scores (PRSs) might enable more efficient targeting of existing cancer screening programmes and enable extension into new age ranges and disease types. To address this proposition, we present an overview of the performance of PRS tools (ie, models and sets of single nucleotide polymorphisms) alongside harms and benefits of PRS-stratified cancer screening for eight example cancers (breast, prostate, colorectal, pancreas, ovary, kidney, lung, and testicular cancer).

Development and Evaluation of a Telephone Communication Protocol for the Delivery of Personalized Melanoma Genomic Risk to the General Population.
Georgina L Fenton et al. J Genet Couns 2017 12 (2) 370-380 (Posted: May 04, 2023 6AM)

This study aimed to develop an online educational program for using PRS for breast and ovarian cancer risk-assessments and evaluate the impact on genetic healthcare providers’ (GHP) attitudes, confidence, knowledge, and preparedness. The educational program comprised of an online module covering theoretical aspects of PRS, and a facilitated virtual workshop with pre-recorded roleplays and case discussions. Data were collected in pre-and post-education surveys.

Cardiovascular Disease Risk Assessment Using Traditional Risk Factors and Polygenic Risk Scores in the Million Veteran Program.
Jason L Vassy et al. JAMA Cardiol 2023 5 (Posted: May 04, 2023 6AM)

Do polygenic risk scores (PRSs) for coronary heart disease and acute ischemic stroke predict incident atherosclerotic cardiovascular disease (ASCVD) events? In an ancestrally diverse, primary prevention sample of almost 80?000 veterans observed for up to 7 years, PRSs were significantly associated with incident myocardial infarction, acute ischemic stroke, and cardiovascular death. Discrimination was modest overall but greater among women and younger participants.

Clinical utility of polygenic risk scores: a critical 2023 appraisal
S Koch et al, J Comm Genetics, May 3, 2023 (Posted: May 03, 2023 7AM)

We surveyed the current state of PRSs for various diseases, including breast cancer, diabetes, prostate cancer, coronary artery disease, and Parkinson disease, with an extra focus upon the potential improvement of clinical scores by their combination with PRSs. We observed that the diagnostic and prognostic performance of PRSs alone is consistently low, as expected. Moreover, combining a PRS with a clinical score at best led to moderate improvement of the power of either risk marker. Despite the large number of PRSs reported in the scientific literature, prospective studies of their clinical utility, particularly of the PRS-associated improvement of standard screening or therapeutic procedures, are still rare.

Polygenic risk scores
NHGRI, NIH, 2023 Brand (Posted: Apr 30, 2023 6AM)

Researchers identify genomic variants associated with complex diseases by comparing the genomes of individuals with and without those diseases. The enormous amount of genomic data now available enables researchers to calculate which variants tend to be found more frequently in groups of people with a given disease. There can be hundreds or even thousands of variants per disease. Researchers put this information into a computer and use statistics to estimate how the collection of a person’s variants affect their risk for a certain disease. This yields polygenic risk scores. All of this can be done without knowing the specific genes involved in the complex disease. While we may someday know all the genes involved, researchers can estimate risk now without this link.

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 Brand (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 Brand (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 Brand (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.


Disclaimer: Articles listed in Hot Topics of the Day are selected by Public Health Genomics Branch to provide current awareness of the scientific literature and news. Inclusion in the update does not necessarily represent the views of the Centers for Disease Control and Prevention nor does it imply endorsement of the article's methods or findings. CDC and DHHS assume no responsibility for the factual accuracy of the items presented. The selection, omission, or content of items does not imply any endorsement or other position taken by CDC or DHHS. Opinion, findings and conclusions expressed by the original authors of items included in the Clips, or persons quoted therein, are strictly their own and are in no way meant to represent the opinion or views of CDC or DHHS. References to publications, news sources, and non-CDC Websites are provided solely for informational purposes and do not imply endorsement by CDC or DHHS.