517 hot topic(s) found with the query "Genetic risk score or polygenic"
Managing differential performance of polygenic risk scores across groups: Real-world experience of the eMERGE Network
(Posted: May 01, 2024 1PM)
From the abstract: "The differential performance of polygenic risk scores (PRSs) by group is one of the major ethical barriers to their clinical use. It is also one of the main practical challenges for any implementation effort. The social repercussions of how people are grouped in PRS research must be considered in communications with research participants, including return of results. Here, we outline the decisions faced and choices made by a large multi-site clinical implementation study returning PRSs to diverse participants in handling this issue of differential performance. "
Polygenic scores for longitudinal prediction of incident type 2 diabetes in an ancestrally and medically diverse primary care physician network: a patient cohort study
(Posted: Apr 29, 2024 11AM)
From the article: "Genetic information, if available, could improve T2D prediction among patients lacking measured clinical risk factors. Genome-wide association studies (GWAS) have identified hundreds of unique loci associated with T2D, the results of which can be used to calculate polygenic scores (PGS) that model genetic risk independently of established clinical risk factors including family history. Previous work has evaluated how PGS can be used within healthcare systems, but analyses have been largely cross-sectional in biobanks of mostly European ancestry, limiting the generalizability of results to a more ancestrally and medically diverse US healthcare system. "
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. "
Integration of pathologic characteristics, genetic risk and lifestyle exposure for colorectal cancer survival assessment
J Xin et al, Nature Comm, April 8, 2024
(Posted: Apr 09, 2024 8AM)
From the abstract: "The development of an effective survival prediction tool is key for reducing colorectal cancer mortality. Here, we apply a three-stage study to devise a polygenic prognostic score (PPS) for stratifying colorectal cancer overall survival. Leveraging two cohorts of 3703 patients, we first perform a genome-wide survival association analysis to develop eight candidate PPSs. Further using an independent cohort with 470 patients, we identify the 287 variants-derived PPS (i.e., PPS287) achieving an optimal prediction performance [hazard ratio (HR) per SD?=?1.99, P?=?1.76?×?10-8], accompanied by additional tests in two external cohorts, with HRs per SD of 1.90 (P?=?3.21?×?10-14; 543 patients) and 1.80 (P?=?1.11?×?10-9; 713 patients). Notably, the detrimental impact of pathologic characteristics and genetic risk could be attenuated by a healthy lifestyle, yielding a 7.62% improvement in the 5-year overall survival rate. "
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. "
Polygenic risk scores, radiation treatment exposures and subsequent cancer risk in childhood cancer survivors.
Todd M Gibson et al. Nat Med 2024 3
(Posted: Mar 12, 2024 0PM)
From the abstract: "Survivors of childhood cancer are at increased risk for subsequent cancers attributable to the late effects of radiotherapy and other treatment exposures; thus, further understanding of the impact of genetic predisposition on risk is needed. Combining genotype data for 11,220 5-year survivors from the Childhood Cancer Survivor Study and the St Jude Lifetime Cohort, we found that cancer-specific polygenic risk scores (PRSs) derived from general population, genome-wide association study, cancer loci identified survivors of European ancestry at increased risk of subsequent basal cell carcinoma (odds ratio per s.d. of the PRS: OR?=?1.37, 95% confidence interval (CI)?=?1.29–1.46), female breast cancer (OR?=?1.42, 95% CI?=?1.27–1.58), thyroid cancer (OR?=?1.48, 95% CI?=?1.31–1.67), squamous cell carcinoma (OR?=?1.20, 95% CI?=?1.00–1.44) and melanoma (OR?=?1.60, 95% CI?=?1.31–1.96) "
Genetics of chronic respiratory disease.
Ian Sayers et al. Nat Rev Genet 2024 3
(Posted: Mar 07, 2024 8AM)
From the abstract: "Chronic respiratory diseases, such as chronic obstructive pulmonary disease (COPD), asthma and interstitial lung diseases are frequently occurring disorders with a polygenic basis that account for a large global burden of morbidity and mortality. Recent large-scale genetic epidemiology studies have identified associations between genetic variation and individual respiratory diseases and linked specific genetic variants to quantitative traits related to lung function. "
Multi-ancestry polygenic mechanisms of type 2 diabetes
K Smith et al, Nature Medicine, March 6, 2024
(Posted: Mar 06, 2024 9AM)
From the abstract: "Type 2 diabetes (T2D) is a multifactorial disease with substantial genetic risk, for which the underlying biological mechanisms are not fully understood. In this study, we identified multi-ancestry T2D genetic clusters by analyzing genetic data from diverse populations in 37 published T2D genome-wide association studies representing more than 1.4 million individuals. We implemented soft clustering with 650 T2D-associated genetic variants and 110 T2D-related traits, capturing known and novel T2D clusters with distinct cardiometabolic trait associations across two independent biobanks. "
Researchers optimize genetic tests for diverse populations to tackle health disparities
NIH, February 2024
(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."
Genomic risk scores in prostate cancer: polygenic yes, but are they poly-ancestral?
Arnab Basu et al. J Natl Cancer Inst 2024 2
(Posted: Feb 22, 2024 9AM)
From the article: "Today, these new studies are providing critical data necessary to update our risk evaluation tools in an intentionally inclusive way and advance the quality of care for all patients with prostate cancer. A recent study focuses on germline risk scores for prostate cancer diagnosis, but closer investigation of genomic data holds the promise of improving outcomes for patients of African ancestry at all stages of their disease course. "
Cancer risks among first-degree relatives of women with a genetic predisposition to breast cancer.
Qingyang Xiao et al. J Natl Cancer Inst 2024 2
(Posted: Feb 22, 2024 9AM)
From the abstract: "We used women from two Swedish cohorts (KARMA and pKARMA), including 28,362 women with genotyping data and 13,226 with sequencing data. Using Swedish Multi-Generation Register, we linked these women to 133,389 first-degree relatives. Associations between protein-truncating variants (PTVs) in 8 risk genes and breast cancer polygenic risk score (PRS) in index women and cancer risks among their relatives were modeled via Cox regression.Female relatives of index women who were PTV carriers in any of the 8 risk genes had an increased breast cancer risk compared to those of non-carriers (HR 1.85, 95% CI: 1.52-2.27), with the strongest association found for PTVs in BRCA1/2. "
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. "
Combining rare and common genetic variants improves population risk stratification for breast cancer
A Bolze et al, Genetics in Medicine Open, February 2, 2024
(Posted: Feb 05, 2024 11AM)
From the abstract: " This study aimed to evaluate the performance of different genetic screening approaches to identify women at high-risk of breast cancer in the general population. We retrospectively studied 25,591 women with available electronic health records and genetic data, participants in the Healthy Nevada Project. Family history of breast cancer was ascertained on or after the record of breast cancer for 78% of women with both, indicating that this risk assessment method is not being properly utilized for early screening. Genetics offered an alternative method for risk assessment. 11.4% of women were identified as high-risk based on possessing a predicted loss-of-function (pLOF) variant in BRCA1, BRCA2 or PALB2 (hazard ratio = 10.4, 95% confidence interval: 8.1-13.5), or a pLOF variant in ATM or CHEK2 (HR = 3.4, CI: 2.4-4.8), or being in the top 10% of the polygenic risk score (PRS) distribution (HR = 2.4, CI: 2.0-2.8). "
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. "
Genetic risk and likelihood of prostate cancer detection on first biopsy by ancestry.
Kyung Min Lee et al. J Natl Cancer Inst 2024 1
(Posted: Jan 20, 2024 10AM)
From the abstract: "This cross-sectional retrospective analysis examines the association between a polygenic hazard score (PHS290) and risk of prostate cancer diagnosis upon first biopsy in male Veterans using two-sided tests. Our analysis included 36,717 Veterans (10,297 of African ancestry). Unadjusted rates of positive first prostate biopsy increased with higher genetic risk (low risk: 34%, high risk: 58%; p?<?.001). Among men of African ancestry, higher genetic risk was associated with increased prostate cancer detection on first biopsy (OR 2.18, 95% CI 1.93-2.47), but the effect was stronger among men of European descent (OR 3.89, 95% CI 3.62-4.18). "
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."
Genomic medicine year in review: 2023.
Teri A Manolio et al. Am J Hum Genet 2023 12 (12) 1992-1995
(Posted: Dec 14, 2023 8AM)
From the article: "Highlighted papers in genomic medicine implementation research in 2023 continued several themes from earlier years, particularly in diagnostic testing of critically ill infants, genetic diagnosis of rare syndromes, and prenatal and population-based screening for monogenic syndromes. Pharmacogenomics was also highlighted with the first large-scale, multi-country clinical trial of multiple gene-drug pairs. The success of the first CRISPR-Cas9-based therapeutic trial in sickle cell disease and the independence of polygenic risk scores and family history in complex disease risk assessment were also highlighted, as were the high rate of insurance denials for exome sequencing that frequently turned out to be diagnostic. "
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. "
Personalized Initial Screening Age for Colorectal Cancer in Individuals at Average Risk.
Xuechen Chen et al. JAMA Netw Open 2023 10 (10) e2339670
(Posted: Oct 27, 2023 9AM)
From the abstract: "How can risk variation in individuals without a family history of colorectal cancer (CRC) be translated into personalized starting ages of screening? In this cohort study of 242?779 participants with no previous screening for and no family history of CRC, derivation of risk-adapted starting ages of screening used 2 major CRC risk indicators, sex and a polygenic risk score (PRS), based on the risk advancement period concept. Risk-adapted starting ages varied by as much as 24 years between men in the highest PRS decile and women in the lowest PRS decile, even among individuals at average risk. "
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. "
Do polygenic risk scores add to clinical data in predicting pancreatic cancer? a scoping review.
Louise Wang et al. Cancer Epidemiol Biomarkers Prev 2023 8
(Posted: Sep 16, 2023 1PM)
From the abstract: "21 studies examined associations between a PC-specific PRS and PC. Seven studies evaluated risk factors beyond age and sex. Three studies evaluated the change in discrimination associated with the addition of PRS to routine risk factors and reported improvements [(AUCs: 0.715 to 0.745; AUC 0.791 to 0.830; AUC from 0.694 to 0.711]. Limitations to clinical applicability included using source populations younger/healthier than those at risk for PC (n=10), exclusively of European ancestry (n=13), or controls without relevant exposures (n=1). While most studies of PC-specific PRS did not evaluate the independent discrimination of PRS for PC beyond routine risk factors, three that did showed improvements in discrimination. "
Rare variant and polygenic analyses of amyotrophic lateral sclerosis in the French-Canadian genome
JP Ross et al, Genetics in Medicine, August 25, 2023
(Posted: Aug 25, 2023 8AM)
From the abstract: "The genetic etiology of amyotrophic lateral sclerosis (ALS) includes few rare, large-effect variants and potentially many common, small-effect variants per case. The genetic risk liability for ALS might require a threshold comprised of a certain amount of variants. Here, we tested the degree to which risk for ALS was affected by rare variants in ALS genes, polygenic risk score, or both."
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."
Assessing a Polygenic Risk Score for Lung Cancer Susceptibility in Non-Hispanic White and Black Populations.
Matthew R Trendowski et al. Cancer Epidemiol Biomarkers Prev 2023 8
(Posted: Aug 15, 2023 2PM)
Polygenic risk scores (PRS) have become an increasingly popular approach to evaluate cancer susceptibility, but have not adequately represented Black populations in model development. Methods: We used a previously published lung cancer PRS based on 80 SNPs associated with lung cancer risk in the OncoArray cohort and validated in UK Biobank. The PRS was evaluated for association with lung cancer risk adjusting for age, sex, total pack-years, family history of lung cancer, history of COPD, and the top five principal components for genetic ancestry.
How are genetics, lifestyles, and cardiovascular and thromboembolic events associated following COVID-19 diagnosis?
TS Lomte, News Medical, August 2023
(Posted: Aug 11, 2023 11AM)
A recent study published in Nature Communications evaluated the associations between host genetics, lifestyle factors, and cardiovascular and thromboembolic events (CVEs) after coronavirus disease 2019 (COVID-19). Although prophylactic coagulation is recommended for hospitalized COVID-19 patients, mixed evidence exists for milder ambulatory and more critical COVID-19 patients. Polygenic risk scores (PRSs) have been proposed for early risk stratification and precision medicine. Whether genetic susceptibility to chronic CVD predisposes COVID-19 patients to CVE complications is unknown.
Preliminary Evidence for Genetic Nurture in Depression and Neuroticism Through Polygenic Scores.
Justin D Tubbs et al. JAMA Psychiatry 2023 6 (8) 832-841
(Posted: Aug 03, 2023 6PM)
Is there evidence for parental genetic nurture in the risk of depression and neuroticism? In this cross-sectional study of 38?702 offspring, results from polygenic score (PGS) modeling provide limited preliminary evidence of genetic nurture in depression and neuroticism. Parental PGSs for depression were significantly associated with offspring neuroticism, with a regression estimate two-thirds that of the offspring’s own PGS, whereas results suggest that previous associations between cannabis use PGS and depression may be noticeably biased by parental genetic nurture.
Regulating Direct-to-Consumer Polygenic Risk Scores
JS Sherkow et al, JAMA, August 3, 2023
(Posted: Aug 03, 2023 6PM)
PGSs are available to consumers both through typical direct-to-consumer (DTC) genetic tests, where the consumer provides a genetic sample to be sequenced and analyzed by a company or as pure software, where consumers upload their previously sequenced genetic data to be analyzed. Although the US Food and Drug Administration (FDA) actively regulates DTCs, many DTC-PGSs evade regulatory scrutiny as general wellness products or unregulated software over which the FDA declines to exercise enforcement.
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.
Breast cancer risk stratification using genetic and non-genetic risk assessment tools for 246,142 women in the UK Biobank.
PJ Ho et al, Genetics in Medicine, Jun e 15, 2023
(Posted: Jun 16, 2023 1PM)
We studied the overlap of predicted high-risk individuals among 246,142 women enrolled in the UK Biobank. Risk predictors assessed include the Gail model (Gail), BC family history (FH, binary), BC polygenic risk score (PRS), and presence of LoF in BC predisposition genes. The best-performing combinatorial model comprises a union of high-risk women identified by PRS, FH, and, LoF (AUC2-year [95% CI]: 62.2 [60.8 to 63.6]). Assigning individual weights to each risk prediction tool increased discriminatory ability.
Evaluating approaches for constructing polygenic risk scores for prostate cancer in men of African and European ancestry.
Burcu F Darst et al. Am J Hum Genet 2023 6
(Posted: Jun 15, 2023 8AM)
Genome-wide polygenic risk scores (GW-PRSs) have been reported to have better predictive ability than PRSs based on genome-wide significance thresholds across numerous traits. We compared the predictive ability of several GW-PRS approaches to a recently developed PRS of 269 established prostate cancer-risk variants from multi-ancestry GWASs and fine-mapping studies. The investigation suggests that current GW-PRS approaches may not improve the ability to predict prostate cancer risk compared to the PRS269 developed from multi-ancestry GWASs and fine-mapping.
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.
Genetically adjusted PSA levels for prostate cancer screening.
Linda Kachuri et al. Nat Med 2023 6
(Posted: Jun 02, 2023 6AM)
In this study, we discovered 128 genome-wide significant associations (P?<?5?×?10-8) in a multi-ancestry meta-analysis of 95,768 men and developed a PSA polygenic score (PGSPSA) that explains 9.61% of constitutive PSA variation. Genetically adjusted PSA was more predictive of aggressive prostate cancer (odds ratio (OR)?=?3.44, P?=?6.2?×?10-14, area under the curve (AUC)?=?0.755) than unadjusted PSA (OR?=?3.31, P?=?1.1?×?10-12, AUC?=?0.738) in 106 cases and 23,667 controls. Compared to a prostate cancer PGS alone (AUC?=?0.712), including genetically adjusted PSA improved detection of aggressive disease (AUC?=?0.786, P?=?7.2?×?10-4). Our findings highlight the potential utility of incorporating PGS for personalized biomarkers in prostate cancer screening.
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.
Prediction of breast cancer risk for sisters of women attending screening.
Xinhe Mao et al. J Natl Cancer Inst 2023 5
(Posted: May 30, 2023 7AM)
We included 53,051 women from the KARMA study. Established risk factors were derived using self-reported questionnaires, mammograms, and SNP genotyping. Using the Swedish Multi-Generation Register, we identified 32,198 sisters of the KARMA women. We found that a higher breast cancer polygenic risk score, a history of benign breast disease, and higher breast density in women were associated with an increased risk of breast cancer for both women and their sisters.
Polygenic prediction of preeclampsia and gestational hypertension.
Michael C Honigberg et al. Nat Med 2023 5
(Posted: May 30, 2023 6AM)
Here we tested the association of maternal DNA sequence variants with preeclampsia in 20,064 cases and 703,117 control individuals and with gestational hypertension in 11,027 cases and 412,788 control individuals across discovery and follow-up cohorts using multi-ancestry meta-analysis. Altogether, we identified 18 independent loci associated with preeclampsia/eclampsia and/or gestational hypertension, 12 of which are new (for example, MTHFR–CLCN6, WNT3A, NPR3, PGR and RGL3), including two loci (PLCE1 and FURIN) identified in the multitrait analysis.
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.
Assessing the potential of polygenic scores to strengthen medical risk prediction models of COVID-19.
Aldo Córdova-Palomera et al. PLoS One 2023 5 (5) e0285991
(Posted: May 27, 2023 6AM)
In UK Biobank participants of European ancestry, the model achieved a relatively high performance (area under the receiver operating characteristic curve ~90%). Polygenic scores for COVID-19 computed from summary statistics of the Covid19 Host Genetics Initiative displayed significant associations with COVID-19 in the UK Biobank (p-values as low as 3.96e-9, all with R2 under 1%), but were unable to robustly improve predictive performance of the non-genetic factors.
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).
Polygenic risk score-based phenome-wide association study identifies novel associations for Tourette syndrome.
Pritesh Jain et al. Transl Psychiatry 2023 2 (1) 69
(Posted: May 10, 2023 6AM)
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
(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.
Potential utility of risk stratification for multicancer screening with liquid biopsy tests
ES Kim et al, NPJ Precision Oncology, April 22, 2023
(Posted: Apr 23, 2023 0PM)
We develop and validate sex-specific pan-cancer risk scores (PCRSs), defined by the combination of body mass index, smoking, family history of cancers, and cancer-specific polygenic risk scores (PRSs), to predict the absolute risk of developing at least one of the many common cancer types. We demonstrate the added value of PRSs in improving the predictive performance of the risk factors only model and project the positive and negative predictive values for two promising multicancer screening tests across risk strata defined by age and PCRS.
Breast cancer polygenic risk scores derived in White European populations are not calibrated for women of Ashkenazi Jewish descent.
E Roberts et al, Genetics in Medicine, April 12, 2023
(Posted: Apr 13, 2023 6AM)
Deep learning-based polygenic risk analysis for Alzheimer's disease prediction.
Xiaopu Zhou et al. Communications medicine 2023 4 (1) 49
(Posted: Apr 07, 2023 8AM)
The polygenic nature of Alzheimer’s disease (AD) suggests that multiple variants jointly contribute to disease susceptibility. As an individual’s genetic variants are constant throughout life, evaluating the combined effects of multiple disease-associated genetic risks enables reliable AD risk prediction. Deep learning models outperform other statistical models for modeling AD risk. Moreover, the polygenic risk derived from the deep learning models enables the identification of disease-associated biological pathways and the stratification of individuals according to distinct pathological mechanisms.
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.
Multiomic signatures of body mass index identify heterogeneous health phenotypes and responses to a lifestyle intervention.
Kengo Watanabe et al. Nature medicine 2023 3
(Posted: Mar 22, 2023 7AM)
We report an atlas of cross-sectional and longitudinal changes in 1,111 blood analytes associated with variation in body mass index (BMI), as well as multiomic associations with host polygenic risk scores and gut microbiome composition, from a cohort of 1,277 individuals enrolled in a wellness program (Arivale). Machine learning model predictions of BMI from blood multiomics captured heterogeneous phenotypic states of host metabolism and gut microbiome composition better than BMI, which was also validated in an external cohort (TwinsUK). Moreover, longitudinal analyses identified variable BMI trajectories for different omics measures in response to a healthy lifestyle intervention.
Limitations, concerns and potential: attitudes of healthcare professionals toward preimplantation genetic testing using polygenic risk scores
M Siermann et al, EJHG, March 20, 2023
(Posted: Mar 21, 2023 9AM)
We found that most healthcare professionals were concerned about the prematurity of introducing PGT-P into clinical practice. They had various ethical considerations, such as concerns related to validity and utility of PGT-P, limited embryos and options, and difficulties for prospective parents regarding comprehension and informed decision-making. Positive aspects were also identified, e.g., regarding reproductive autonomy and potential health benefits. Overall, most healthcare professionals considered that clinical implementation of PGT-P is premature.
Identifying individuals at extreme risk of venous thromboembolism using polygenic risk scores.
Michael Chong et al. Nature genetics 2023 3 (3) 358-360
(Posted: Mar 18, 2023 3PM)
Current risk assessment and treatment strategies for venous thromboembolism (VTE) consider genetic factors only in a limited way. New work shows a more pervasive role of common variants in VTE risk, inspiring genetic predictors that surpass and complement individual clinical risk factors and monogenic thrombophilia testing.
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.
A Polygenic Risk Score for Prostate Cancer Risk Prediction.
Kerry R Schaffer et al. JAMA internal medicine 2023 3
(Posted: Mar 07, 2023 6PM)
In this study, a prostate cancer polygenic risk score did not improve risk prediction of aggressive prostate cancer compared with a contemporary clinical risk predictor. Although the PRS269 improved model discrimination for all cancers, improvement was less than has been observed for other validated prostate cancer biomarker predictors such as the Prostate Health Index.
Bringing Prostate Cancer Polygenic Risk Scores to the Clinic.
Robert J Klein et al. JAMA internal medicine 2023 3
(Posted: Mar 07, 2023 6PM)
The PRS as currently formulated will not enhance clinical decision-making. There is a need to demonstrate accuracy and utility—defined for the relevant clinical context—before rolling such scores out on a large scale. Given the experience with PSA testing, where a marker for any prostate cancer resulted in detection of many indolent cancers that did not need treatment, care will need to be taken that any PRS that makes it to the clinic can discriminate between indolent and potentially lethal prostate cancer.
Evaluation of polygenic risk scores to differentiate between type 1 and type 2 diabetes.
Muhammad Shoaib et al. Genetic epidemiology 2023 2
(Posted: Mar 04, 2023 9AM)
We evaluated PRS models for T1D and T2D in European genetic ancestry participants from the UK Biobank (UKB) and then in the Michigan Genomics Initiative (MGI). Specifically, we investigated the utility of T1D and T2D PRS to discriminate between T1D, T2D, and controls in unrelated UKB individuals of European ancestry. We derived PRS models using external non-UKB GWAS. The T1D PRS model with the best discrimination between T1D cases and controls (area under the receiver operator curve [AUC]?=?0.805) also yielded the best discrimination of T1D from T2D cases in the UKB (AUC?=?0.792) and separation in MGI (AUC?=?0.686).
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.
Polygenic Risk Scores for Asthma and Allergic Disease Associate with COVID-19 Severity in 9/11 Responders
M Wasczuk et al, MEDRXIV, February 16, 2023
(Posted: Feb 17, 2023 6AM)
Relatively little is known about the associations between PRS and COVID-19 severity or post-acute COVID-19 in community-dwelling individuals. Methods. Participants in this study were 983 World Trade Center responders infected for the first time with SARS-CoV-2. The results indicate that recently developed polygenic biomarkers for asthma, allergic disease, and COVID-19 hospitalization capture some of the individual differences in severity and clinical course of COVID-19 illness in a community population.
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.
Associations Between Polygenic Risk Score Loading, Psychosis Liability, and Clozapine Use Among Individuals With Schizophrenia.
Bochao D Lin et al. JAMA psychiatry 2022 12 (2) 181-185
(Posted: Feb 02, 2023 6AM)
Are polygenic risk scores for schizophrenia (PRS-SCZ) associated with a psychosis liability spectrum and a clinician’s decision to prescribe clozapine?
In this genetic association study with 2344 participants from 2 cohorts, we found that PRS-SCZ loading was highest among individuals with schizophrenia spectrum disorders taking clozapine, followed by those taking other antipsychotics, their relatives, and unrelated healthy controls. In addition, PRS-SCZ was positively associated with a clozapine prescription relative to other antipsychotics.
Association of Polygenic Risk Scores for Hearing Difficulty in Older Adults With Hearing Loss in Mid-Childhood and Midlife: A Population-Based Cross-sectional Study Within the Longitudinal Study of Australian Children.
Jing Wang et al. JAMA otolaryngology-- head & neck surgery 2023 1
(Posted: Jan 28, 2023 11AM)
This population-based cross-sectional study, including 1608 children and 1642 adults, nested within the Longitudinal Study of Australian Children found that in contemporaneous population-based samples, PRSs computed from self-reported hearing difficulty in 40- to 69-year-old adults showed some evidence of association with hearing ability in 11- to 12-year-olds and their parents, but minimal evidence of associations with speech reception ability.
Risk assessment for colorectal cancer via polygenic risk score and lifestyle exposure: a large-scale association study of East Asian and European populations.
Junyi Xin et al. Genome medicine 2023 1 (1) 4
(Posted: Jan 25, 2023 8AM)
Using the UK Biobank cohort, we further validated a significant dose-response effect of PRSCSx on incident colorectal cancer, in which the risk was 2.11- and 3.88-fold higher in individuals with intermediate and high PRSCSx than in the low score subgroup (Ptrend = 8.15 × 10-53). Notably, the detrimental effect of being at a high genetic risk could be largely attenuated by adherence to a favorable lifestyle, with a 0.53% reduction in 5-year absolute risk.
Genome-wide meta-analysis identifies 93 risk loci and enables risk prediction equivalent to monogenic forms of venous thromboembolism.
Ghouse Jonas et al. Nature genetics 2023 1
(Posted: Jan 22, 2023 8AM)
We report a genome-wide association study of venous thromboembolism (VTE) incorporating 81,190?cases and 1,419,671?controls sampled from six cohorts. We identify 93?risk loci, of which 62 are previously unreported. Many of the identified risk loci are at genes encoding proteins with functions converging on the coagulation cascade or platelet function. A VTE polygenic risk score (PRS) enabled effective identification of both high- and low-risk individuals.
Prioritizing the detection of rare pathogenic variants in population screening.
Lacaze Paul et al. Nature reviews. Genetics 2023 1
(Posted: Jan 15, 2023 3PM)
Population genomic screening to detect carriers of rare monogenic variants for medically actionable conditions is supported by substantial evidence of clinical utility and cost effectiveness. Much less evidence supports screening by polygenic risk scores, which do not detect rare variants. Using only polygenic scores in population screening initiatives, while ignoring the detection of higher-risk rare monogenic variants, is ill-advised.
Returning integrated genomic risk and clinical recommendations: the eMERGE study
JE Linder et al, Genetics in Medicine, January 8, 2023
(Posted: Jan 09, 2023 6AM)
To enable integrated genetic risk assessment, the eMERGE (electronic MEdical Records and GEnomics) network is enrolling 25,000 diverse individuals in a prospective cohort study across 10 sites. The network developed methods to return cross-ancestry polygenic risk scores (PRS), monogenic risks, family history, and clinical risk assessments via a Genome Informed Risk Assessment (GIRA) report
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.
Association of Inherited Genetic Factors With Drug-Induced Hepatic Damage Among Children With Acute Lymphoblastic Leukemia.
Yang Wenjian et al. JAMA network open 2022 12 (12) e2248803
(Posted: Dec 31, 2022 6AM)
In this genetic association study of 3557 children, adolescents, and young adults receiving ALL therapy, variants in UGT1A1 and PNPLA3 were associated with hyperbilirubinemia and elevated alanine aminotransferase and aspartate aminotransferase levels, respectively. A polygenic risk score–based analysis demonstrated that the UGT1A1 variant was the primary driver of elevated bilirubin levels, while other genetic variants contributed to aminotransferase levels even after adjusting for PNPLA3.
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.
Assessment of Body Mass Index, Polygenic Risk Score, and Development of Colorectal Cancer.
Chen Xuechen et al. JAMA network open 2022 12 (12) e2248447
(Posted: Dec 23, 2022 6PM)
Do associations of excess weight with development of colorectal cancer differ by polygenic risk for colorectal cancer (CRC)? In this case-control study including 9169 participants (5053 CRC cases, 4116 controls), associations of excess weight with risk of CRC were independent of polygenic risk for CRC. The association of obesity with CRC risk was equivalent to that of having a 41-percentiles higher polygenic risk score. The findings of this study could contribute to enhanced quantification and communication of the association of excess weight with CRC.
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.
Genetic futurism.
et al. Nature genetics 2022 12 (12) 1757
(Posted: Dec 16, 2022 8AM)
Large-scale genotyping and phenotyping efforts, including biobanks, have revolutionized our understanding of the genetic architecture of human traits and diseases. Years of ever-larger genome-wide association studies (GWAS) have produced a catalog of genetic variants that contribute to complex traits. A corollary of this research has been the development of personalized polygenic scores (PGS) or polygenic risk scores (PRS).
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.
Integrating genome-wide polygenic risk scores and non-genetic risk to predict colorectal cancer diagnosis using UK Biobank data: population based cohort study
SEW Briggs et al, BMJ, November 2022
(Posted: Nov 14, 2022 7AM)
Integrating polygenic risk scores with QCancer-10 modestly improves risk prediction over use of QCancer-10 alone. Given that QCancer-10 data can be obtained relatively easily from health records, use of polygenic risk score in risk stratified population screening for colorectal cancer currently has no clear justification. The added benefit, cost effectiveness, and acceptability of polygenic risk scores should be carefully evaluated in a real life screening setting before implementation in the general population.
Systematic comparison of family history and polygenic risk across 24 common diseases.
Mars Nina et al. American journal of human genetics 2022 11
(Posted: Nov 10, 2022 6AM)
Covering a large proportion of the burden of non-communicable diseases in adults, we show that family history and PRS are independent and not interchangeable measures, but instead provide complementary information on inherited disease susceptibility. The PRSs explained on average 10% of the effect of first-degree family history, and first-degree family history 3% of PRSs, and PRS effects were independent of both early- and late-onset family history. The PRS stratified the risk similarly in individuals with and without family history.
Polygenic risk scores of endo-phenotypes identify the effect of genetic background in congenital heart disease.
Spendlove Sarah J et al. HGG advances 2022 5 (3) 100112
(Posted: Nov 07, 2022 8AM)
Here we used CHD-phenotype matched genome-wide association study (GWAS) summary statistics from the UK Biobank (UKBB) as our base study and whole-genome sequencing data from the CHD cohort (n1 = 711 trios, n2 = 362 European trios) of the Gabriella Miller Kids First dataset as our target study to develop PRSs for CHD. PRSs estimated using a GWAS for heart valve problems and heart murmur explain 2.5% of the variance in case-control status of CHD.
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.
