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PubMed2026

Polygenic risk score and its role in cancer susceptibility.

BACKGROUND: Polygenic risk score (PRS) has the ability to stratify inherited susceptibility to cancer and, as a complement to monogenic testing, can identify individuals at increased genetic risk even when no pathogenic variant is detected in high- or moderate-penetrance genes. It reflects the combined additive effects of a large number of low-penetrance variants across the genome, and represents a continuum of genetic susceptibility with an approximately normal distribution. Clinically relevant differences are typically observed in individuals in the highest and lowest percentiles of the PRS distribution, while relative risk gradients depend on the cancer type, the specific PRS model, and the reference population used. PRS is not a single test but rather a family of statistical models that differ in their design, predictive performance, and transferability across populations, underscoring the need for external validation and population-specific calibration of absolute risk. Broader implementation is thus still held back by differences between individual PRS models, limited transferability, and the lack of harmonized guidance on indication, reporting, and clinical decision-making. Consequently, clinical use in the European Union remains largely confined to pilot studies and local projects. Within these initiatives, PRS is most commonly applied in two main ways - either as a triage tool for intensified diagnostics or screening in higher-risk groups, or as a component of multifactorial absolute-risk models (e. g. BOADICEA/CanRisk) that integrate PRS with other risk factors such as pathogenic variants in moderate-penetrance genes (e. g. ATM or CHEK2), family history, or lifestyle factors. By refining absolute-risk estimates, PRS may shift individuals across clinical decision thresholds for more intensive surveillance and preventive strategies. AIM: This review summarizes the principles of PRS, the main sources of variability between models, and its potential applications in risk stratification and personalized cancer screening. It also addresses limitations in transferability, the need for calibration, and the currently limited evidence for improvements in hard clinical outcomes.

Humans↗

PubMed2026

Polygenic risk score for early identification of coronary artery disease in a real-world clinical setting within the Latvian patient population.

STUDY OBJECTIVE: Polygenic risk scores (PRS) are increasingly recognized for their potential to improve coronary artery disease (CAD) prediction beyond traditional clinical models. This study evaluated the utility of genome-wide association study (GWAS) - derived PRS and pathway-specific PRS (PS-PRS) in the Latvian population, aiming to assess their association with CAD and compare their predictive performance with conventional risk factors. DESIGN PARTICIPANTS AND MAIN OUTCOME MEASURES: The study included 90 early-onset CAD patients and 43 controls with no evidence of atherosclerotic lesions on coronary angiography, with next-generation sequencing performed. PRS was calculated using 192 single nucleotide variants identified from the CARDIoGRAMplusC4D GWAS meta-analysis. The predictive accuracy of PRS, PS-PRS, clinical risk factors, and their combinations was analyzed via ROC curves. RESULTS: The average age was 48.7 years in CAD patients and 49.8 in controls. CAD patients showed significantly higher PRS (mean 0.31) compared to controls (mean - 0.65; p < 0.0001). PRS alone had moderate discriminatory power (AUC = 0.773), slightly lower than LDL cholesterol (AUC = 0.775) and total cholesterol (AUC = 0.821). Combining clinical risk factors improved prediction (AUC = 0.872), with the highest accuracy when PRS was integrated with all clinical factors (AUC = 0.933). The PRS distributions were significantly elevated in early-onset CAD patients across the angiogenesis/tissue repair pathway (p = 0.00038), inflammation pathway (p = 0.043), vascular remodelling pathway (p = 0.0116), and pathway of genes with unknown function in atherosclerosis (p = 0.0035), but overall PRS demonstrated superior discrimination compared to pathway-specific PRS. CONCLUSIONS: Incorporating PRS enhances early-onset CAD risk prediction. Pathway specific PRS had lower discriminative ability than the overall PRS.

Atherosclerosis↗

PubMed2026

Addition of CAD polygenic risk score to coronary artery calcium score enhances prediction of MACE.

BACKGROUND: Coronary heart disease (CHD) is prevalent in the United States, highlighting the need for accurate risk prediction to inform primary prevention strategies. While multivariate risk models like the Framingham Risk Score and ACC/AHA Pooled Cohort Equations are commonly utilized, novel risk markers, such as the coronary artery calcium score (CACS) and polygenic risk score (PRS), are increasingly gaining recognition. OBJECTIVES: This study aimed to compare the diagnostic utility of CACS and CAD PRS, both individually and in combination, for predicting major adverse cardiovascular events (MACE). METHODS: We conducted a retrospective analysis of a cohort comprising 1,380 predominantly Caucasian participants from the Sanford Health System. CAD PRS was constructed using genetic variants, while CACS was assessed via cardiac computed tomography (CT). Statistical analyses evaluated the relationship between each modality and MACE. RESULTS: Both CAD PRS and CACS were significantly associated with future MACE. Following the adjustment for covariates, the area under the curve (AUC) for both the CACS and PRS models was comparable, indicating similar predictive capabilities for MACE. However, the combination of CAD PRS with CACS significantly enhanced predictive accuracy, outperforming either modality alone. CONCLUSIONS: This study underscores the value of integrating CACS and CAD PRS in predicting MACE. The synergistic effect of CAD PRS combined with CACS markedly improves predictive power. Further research and prospective studies are necessary to validate these findings and assess their clinical implications. Investigating the interactions between PRS and CACS will be crucial for refining cardiovascular risk prediction and optimizing prevention strategies.

cardiac genetics↗

PubMed2026

Obesity Polygenic Risk and Healthy Lifestyle Interactions on Weight Trajectories in Women and Men.

BACKGROUND: Genetics and environmental factors contribute to obesity risk, but the extent to which healthy behaviors can offset genetic susceptibility remains unclear. We examined the interaction between obesity polygenic risk and a composite healthy lifestyle score on body mass index (BMI) trajectories in women and men. METHODS: We analyzed 13 780 women from the Nurses' Health Study and 8242 men from the Health Professionals Follow-Up Study, all of European ancestry and free of major chronic disease at baseline. The lifestyle score comprised American Heart Association Essential 8 components (nonsmoking, physical activity, healthy eating, adequate sleep) plus moderate alcohol intake, modeled as a time-varying variable. A genome-wide polygenic score for BMI was derived from genome-wide association study. Adjusted linear mixed-effects models estimated associations and interactions on biennial BMI measures over up to 26 years. RESULTS: Each SD increase in the polygenic score was associated with 1.80 kg/m2 (95% CI, 1.72-1.87) and 1.12 kg/m2 (95% CI, 1.06-1.19) higher BMI in women and men, respectively. Significant interactions between the polygenic score and healthy lifestyle score (both P<0.05) showed a dose-response attenuation of the genetic effects with healthier lifestyles. Comparing the healthiest with the least healthy lifestyle groups, genetic effects on BMI were 35% lower in women and 28% lower in men. In sensitivity analyses, higher diet quality and physical activity consistently attenuated genetic associations in both cohorts, whereas current smoking showed similar effects in women only. CONCLUSIONS: Adherence to a healthier lifestyle attenuated the association between obesity polygenic risk and BMI in a dose-response manner.

Humans↗

PubMed2025

Predicting Weight Loss After Vertical Sleeve Gastrectomy Using a Whole-genome Sequencing-derived Polygenic Risk Score in the All of Us Cohort.

OBJECTIVE: To create a genome-wide polygenic risk score (PRS) to improve prediction of a 12-month percentage weight loss (WL) after vertical sleeve gastrectomy (VSG). BACKGROUND: Variability in post-VSG WL is not well explained by clinical factors. The All of Us program provides access to a 414,830 short-read whole-genome sequencing resource, enabling unbiased discovery of genetic predictors after VSG. METHODS: VSG counts, demographic, anthropomorphic and vital sign information were obtained from the linked electronic health record. The discovery cohort (DC) included participants from version 7 carried into version 8 while the validation cohort (VC) included those newly added to v8. We defined good responders and nonresponders as having WL±1SD from the mean. Following quality filtering, we applied a 2-stage penalized-regression, followed by elastic-net logistic regression, to identify 1583 stable variants and derive β-weights. We then tested this PRS on the DC into a prediction model. RESULTS: We identified 395 participants in the DC and 336 participants in the VC, respectively. Of these, VSG, 44 were classified as good responders (≥37% WL) and 55 as nonresponders (≤19% WL). In the VC, 55 were classified as good responders and 48 as nonresponders. Adding the PRS to models to clinical predictors increased the area under the curve following logistic regression by 0.03; P <4.3 × 10 -14 , random forest by 0.03; P <9.1 × 10 -7 , decision tree by 0.05; P = 1.2 × 10 -3 , and gradient boosting by 0.08; P <8.3 × 10 -10 . CONCLUSIONS: Use of short-read whole-genome sequencing from All of Us (AoU) can be effectively used to generate PRS to enhance predictive WL accuracy. This work has implications for outcomes of both bariatric surgery and other surgical procedures.

Humans↗

PubMed2026

Baseline Computed Tomography Coronary Angiography and Polygenic Risk Profiles in Adults With Type 2 Diabetes: A Cross-Sectional Analysis From the VOLTAIRE Study.

AIMS: To characterise baseline clinical, anatomical, and genetic cardiovascular risk profiles in participants enrolled in the VOLTAIRE (Evaluation of Polygenic Scores and CT Imaging in Risk Factor Modification in Patients with Type 2 Diabetes) study and examine concordance across these domains. METHODS: This analysis included adults with T2D who completed baseline computed tomography coronary angiography (CTCA) and polygenic risk score (PRS) assessment prior to randomisation in the VOLTAIRE study. Coronary atherosclerosis was evaluated using coronary artery calcium (CAC) score and CTCA-derived stenosis severity. Clinical risk was assessed using the New Zealand Society for the Study of Diabetes 5-year cardiovascular risk calculator. Polygenic risk for coronary artery disease was assessed using a genome-wide PRS and categorised into tertiles. RESULTS: Among 126 participants with T2D (mean age 57.5 ± 8.7 years; 62.7% male), coronary atherosclerotic burden was highly heterogeneous: 34.9% had CAC = 0, whereas 19.8% had CAC ≥ 400. Moderate-to-severe coronary stenosis (≥ 50%) was present in 40.5% of participants overall, including 20.4% of those classified as low clinical risk. PRS distribution was variable (low 37.3%, intermediate 35.7%, high 27.0%). Overlap between anatomical, genetic, and clinical domains was limited, with only 8.7% of participants classified as high risk across all three. CONCLUSIONS: Substantial heterogeneity and limited overlap exist between anatomical, genetic, and clinical cardiovascular risk measures in T2D. These findings support a multimodal approach to risk assessment integrating imaging and genetic profiling. TRIAL REGISTRATION: https://www. CLINICALTRIALS: gov; ID: NCT07091162.

Aged↗

PubMed2026

A polygenic risk score for peripheral artery disease and major adverse limb events.

BACKGROUND AND AIMS: Large-scale genome-wide association studies have identified common genetic variants that predict the risk of peripheral artery disease (PAD). This study assessed whether a polygenic risk score (PRS) is associated with PAD and the incidence of major adverse limb events (MALE) independent of clinical risk factors in patients with established cardiometabolic disease. METHODS: A genetic analysis was performed, pooling individual patient-level data from six TIMI trials. The association of a recently validated PAD PRS with prevalent PAD and the incidence of MALE (acute limb ischaemia, chronic limb-threatening ischaemia, major amputation, or peripheral revascularization) was assessed. RESULTS: A total of 68 816 patients were included in this analysis, with a median follow-up of 2.6 years. Of these, 5986 (8.7%) had known PAD at baseline. After adjusting for clinical risk factors, a higher PAD PRS was independently associated with a 15% greater odds of prevalent PAD (adjusted odds ratio per 1-SD: 1.15 [95% confidence interval 1.12-1.18], P < .0001), a magnitude of risk as strong as established clinical risk factors. A total of 577 patients experienced MALE during follow-up. A higher PAD PRS was associated with a 30% increased risk of MALE (adjusted hazard ratio per 1-SD: 1.30 [1.19-1.42], P < .0001). Adding the PAD PRS to clinical risk factors resulted in a statistically significant but modest improvement in discrimination (area under the curve went from 0.651 to 0.662 P < .0001). CONCLUSIONS: In a broad spectrum of patients with cardiometabolic disease, the PAD PRS is associated with an increased risk of PAD and the incidence of MALE beyond clinical risk factors; however, the improvement in discrimination was statistically significant but clinically modest.

Humans↗

PubMed2025

Coronary Artery Disease-Based Polygenic Risk Score in Early-Onset Acute Myocardial Infarction Subtypes.

BACKGROUND: The coronary artery disease-based polygenic risk score (PRS-CAD) estimates risk of acute myocardial infarction (AMI), but its performance across AMI subtypes in younger individuals, especially women, remains uncertain. OBJECTIVES: The authors assessed PRS-CAD's performance in AMI subtypes. METHODS: We included 2,079 AMI patients aged 18 to 55 years with a 2:1 female-to-male ratio from the VIRGO (Variation in Recovery: Role of Gender on Outcomes of Young Acute Myocardial Infarction Patients) study and 3,761 controls from the MESA (Multi-Ethnic Study of Atherosclerosis) study. AMI subtypes were classified using the VIRGO taxonomy. We evaluated PRS-CAD's association with AMI subtypes using multinomial logistic regression and with 1-year outcomes in AMI subtypes using Cox regression. RESULTS: PRS-CAD was significantly associated with MI due to coronary artery disease (N = 1,876; OR: 1.82 per 1-SD increase; 95% CI: 1.67-1.97; P < 0.001) but not with MI with nonobstructive coronary artery disease (N = 188; OR: 1.13 per 1-SD increase; 95% CI: 0.96-1.34; P = 0.14). PRS-CAD's performance did not differ by sex. A 1-SD increase in PRS-CAD was associated with higher risk of 1-year hospitalization or death in patients with MI with nonobstructive coronary artery disease (HR: 1.50; 95% CI: 1.08-2.10; P = 0.02) but not in patients with MI due to coronary artery disease (HR: 0.98; 95% CI: 0.91-1.07; P = 0.67). CONCLUSIONS: PRS-CAD's association with AMI varied by subtype but not by sex in young adults, warranting caution in application.

acute myocardial infarction↗

PubMed2026

Assessing the comorbidity between asthma and depression through polygenic risk scoring and time-to-event models.

BACKGROUND: Patients with asthma have an increased risk of developing depression, affecting their quality of life. To date, the processes contributing to this comorbidity remain unclear. METHODS: We integrated two large genome-wide association studies (88,486 patients with asthma and 447,859 controls; 412,024 patients with depression and 1,587,577 controls) with cross-sectional and longitudinal information available from the All of Us Research Program (N = 87,167) through polygenic risk scoring (PRS), Cox proportional-hazards models, one-sample Mendelian randomization (MR), and gene-set and drug-repurposing analyses. RESULTS: We observed that depression PRS was associated with increased asthma risk (hazard ratio, HR = 1.13, 95% CI = 1.09-1.17), also when accounting for comorbidity status (HR = 1.08, 95% CI = 1.04-1.12). Conversely, the effect of asthma PRS was null after accounting for comorbidity status. One-sample MR analysis showed an effect of depression genetic liability on asthma, ranging from beta = 0.36 ± 0.03 when considering a linear relationship to beta = 3.21 ± 0.31 when considering possible nonlinear relationships. Conversely, the effect of asthma genetic risk on depression was null after accounting for potential confounders. The gene-set analyses showed that asthma and depression polygenic risks share biological processes, molecular functions, and cellular components related to the immune system and the lung-brain axis. CONCLUSIONS: Genetic predisposition contributes to asthma-depression comorbidity through direct effects and shared pathogenic processes. These findings highlight the potential to develop targeted interventions to prevent and treat the co-occurrence of respiratory and neuropsychiatric disorders.

Comorbidity↗

PubMed2026

Polygenic risk scores and lifestyle factors predicting new onset of type 2 diabetes in the Japanese general population.

PURPOSE: This study investigated the association of polygenic risk scores (PRS) and lifestyle factors with type 2 diabetes mellitus development in Japanese populations and evaluated whether PRS can improve diabetes risk prediction beyond traditional risk factors. METHODS: We conducted a cross-sectional and a longitudinal study using the Shika resident cohort (n = 895) and the Toshiba worker cohort (n = 7019), respectively. Participants were categorized into low, intermediate, and high genetic risk groups using PRS constructed with genome-wide association study data from East Asian populations. We defined diabetes based on hemoglobin A1c, fasting blood glucose, self-reported diagnosis, or medication use. The associations of PRS and lifestyle factors with diabetes development were analyzed using multivariate logistic regression and Cox proportional hazards models. RESULTS: Higher PRS were associated with increased diabetes risk in both cohorts (resident cohort: odds ratio 4.51, 95% CI 2.53-8.04; worker cohort: hazard ratio 1.50, 95% CI 1.23-1.83 for high vs low PRS), which remained consistent across age, body mass index, and comorbidities. Regular exercise, absence of hypertension, and absence of dyslipidemia were associated with lower diabetes risk, particularly in the high PRS group. The addition of PRS to conventional prediction models improved the discrimination of diabetes risk. MAIN CONCLUSION: PRS are associated with diabetes risk in Japanese general populations, independent of traditional risk factors. Nonetheless, healthy lifestyle habits may reduce diabetes risk even among genetically susceptible individuals, which support the utility of PRS for personalized diabetes risk assessment and prevention strategies.

Adult↗

PubMed2026

Genetic Susceptibility to Incisional Hernia Evaluation of Hernia Polygenic Risk Scores.

OBJECTIVES: Incisional hernia (IH) affects 13-30% of people after abdominal surgery, resulting in substantial morbidity and costs. While clinical risk factors have been studied extensively, genomic risk for IH is incompletely understood. We aimed to evaluate the impact of polygenic risk scores (PRS) on IH risk prediction. METHODS: We created and evaluated three PRS for abdominal hernia, ventral hernia and latent hernia susceptibility for prediction of IH in an institutional biobank. The primary outcome was defined as the diagnosis or repair of an IH based on ICD-9/10-CM/PCS and CPT codes. Clinical covariates included age, sex, body mass index (BMI), smoking status, index procedure type, and perioperative surgical site infection. A phenome-wide association study (PheWAS) was performed to assess clinical associations with increased PRS. We then tested the ability of the PRS to improve prediction for IH by modeling clinical covariates with and without PRS in patients who underwent abdominal surgery. Model performance was assessed using 10 iterations of 5-fold cross-validation to estimate Brier scores and area under the receiver operating characteristic curve (AUROC), which were compared using cross-model Bayesian analysis of variance. RESULTS: In 55,809 subjects, assessed PRS was significantly associated with incisional, umbilical, and ventral hernia on PheWAS, with 1.19 greater odds of developing IH per 1-SD increase in PRS (95% CI: 1.13-1.25, P < 0.001). Of 9,909 subjects who underwent qualifying abdominal surgery, 706 developed IH. In this cohort, the latent hernia susceptibility PRS was associated with a 16% increased hazard of developing IH per 1-SD increase (HR 1.16; 95% CI: 1.07-1.26; P < 0.001). Compared to a predictive model using clinical covariates (Brier score = 0.047, 95% CI: 0.046-0.048; AUROC = 0.660, 95% CI: 0.653-0.666), addition of the PRS showed similar Brier score and AUROC estimates (Brier score = 0.047, 95% CI: 0.046-0.048; AUROC: 0.667, 95% CI: 0.661-0.673) at five years. Cross-model Bayesian analysis demonstrated >99% probability of practical equivalence when trying to detect a difference of ≥ 0.02. CONCLUSION: All three PRS for hernia were independently associated with IH, suggesting that genomic factors contribute significantly to IH development. However, none of the three PRS meaningfully improved clinical IH risk prediction in patients who underwent abdominal surgery. This suggests that clinical comorbidities and surgical techniques may be equally as important as genomic architecture.

Bayesian analysis↗

PubMed2026

Harnessing Polygenic Risk Scores to Refine Venous Thromboembolism Risk Stratification.

BACKGROUND: Venous thromboembolism (VTE) is a major cause of morbidity in patients of all ages. Despite growing interest in polygenic risk scores (PRS) for VTE, their utility remains understudied. Our objective was to evaluate the independent impact of a PRS on VTE susceptibility in adults and children. METHODS: We completed a retrospective, case-control study of two separate cohorts with evaluation of three VTE PRS models, with the primary analysis focused on a 293 single nucleotide polymorphism (SNP) PRS. The adult cohort included 597 VTE cases and 31 998 controls, and the pediatric cohort included 109 cases and 448 controls, both obtained from a de-identified databank with linked genetic data. Separate adult and pediatric multivariable logistic regressions were performed to measure the association of risk factors with VTE. RESULTS: Higher PRS in adults was significantly associated with increased odds of VTE, with each 1-standard deviation increase in PRS conferring an adjusted odds ratio of 1.25 (OR = 1.25, 95% CI 1.15-1.36, p < 0.001). Leading risk factors for adults were cancer (OR = 2.43, 95% CI: 2.04-2.89, p < 0.001) and recent surgery (OR = 2.16, 95% CI: 1.83-2.54, p < 0.001). The standardized PRS also exhibited increased risk for VTE in children (OR = 1.38, 95% CI 1.10-1.74, p = 0.003). Central venous catheterization (OR = 5.65, 95% CI 3.40-9.50, p < 0.001) was the foremost risk factor for pediatric VTE. CONCLUSION: VTE in adults and children is multifactorial, with clinical and genome-wide risk factors contributing. PRS may serve as a valuable adjunct to clinical risk factors for VTE risk stratification.

Humans↗

PubMed2024

Cost-effectiveness of population-wide genomic screening for Lynch Syndrome and polygenic risk scores to inform colorectal cancer screening.

PURPOSE: Genomic screening to identify individuals with Lynch Syndrome (LS) and those with a high polygenic risk score (PRS) promises to personalize colorectal cancer (CRC) screening. Understanding its clinical and economic impact is needed to inform screening guidelines and reimbursement policies. METHODS: We developed a Markov model to simulate individuals over a lifetime. We compared LS+PRS genomic screening with standard of care (SOC) for a cohort of US adults at age 30. The Markov model included health states of no CRC, CRC stages (A-D), and death. We estimated incidence, mortality, and discounted economic outcomes of the population under different interventions. RESULTS: Screening 1000 individuals for LS+PRS resulted in 1.36 fewer CRC cases and 0.65 fewer deaths compared with SOC. The incremental cost-effectiveness ratio was $124,415 per quality-adjusted life year; screening had a 69% probability of being cost-effective using a willingness-to-pay threshold of $150,000/quality-adjusted life year . Setting the PRS threshold at the 90th percentile of the LS+PRS screening program to define individuals at high risk was most likely to be cost-effective compared with 95th, 85th, and 80th percentiles. CONCLUSION: Population-level LS+PRS screening is marginally cost-effective, and a threshold of 90th percentile is more likely to be cost-effective than other thresholds.

Humans↗

PubMed2026

bioETH-PRS: confidential polygenic risk scoring with smart contracts on an FHE-enabled blockchain.

Polygenic risk scores (PRSs) aggregate genetic effect estimates to predict disease susceptibility, yet calculating one through an external service can require exposing raw genotype data. Homomorphic encryption hides those data during the calculation but, in prior work, still places a designated evaluator in a position of trust. We present bioETH-PRS, a protocol that replaces the evaluator with publicly auditable smart contracts on a blockchain supporting Fully Homomorphic Ethereum Virtual Machine (fhEVM). Using integer-exact encrypted arithmetic, bioETH-PRS computes the PRS dot product entirely in the encrypted domain, so genotype dosages and, at the model provider's discretion, the GWAS weights stay hidden from the parties performing the computation. A fixed-point encoding represents signed weights as nonnegative integers within a bound that rules out overflow, recovering the score to the precision of the published weights. A four-contract architecture separates data custody, model publication, computation, and output release, and supports both a classic path that stores encrypted inputs and an appreciably cheaper streaming path that discards them. A release oracle can return a randomized risk category instead of the raw score, limiting what a repeated querier learns. Prototype evaluation on real GWAS fixtures, including a run on a public testnet, shows cost growing linearly with variant count and suggests the approach may be practical where transaction fees are low. Trust is redistributed rather than removed: the system still depends on the contracts, the blockchain, and the fhEVM services. We evaluate additive models of moderate size, not genome-wide or clinical use.

Blockchain↗

PubMed2025

Polygenic risk scores in the clinic: Health-system leaders and primary care providers weigh in.

PURPOSE: The fourth phase of the Electronic Medical Records and Genome Network is testing the return of 10 polygenic risk scores (PRS) across multiple clinics. Understanding the perspectives of health-system leaders and frontline clinicians can inform plans for implementation of PRS. METHODS: A total of 15 health-system leaders and 20 primary care providers took part in semistructured interviews. A descriptive thematic analysis was performed. RESULTS: Interviewees generally perceived PRS to have limited clinical utility, although they saw value in the potential to identify and act upon risks that are not otherwise detectable. Perceived potential drawbacks included negative psycho-emotional effects on patients, unnecessary follow-up, distracting from population health priorities, opportunity costs, and medicolegal liability. Implementation considerations included increased encounter time and the need for clinical practice guidelines, provider training, care coordination, and point-of-care resources. CONCLUSION: Participants generally expressed favorable views of precision medicine and also identified potential challenges to introducing PRS in clinical care. Implementation will require careful assessment of clinical utility vs usual care; ensuring that the benefit to be realized merits the time and resources required to interpret, return, and act on results and developing guidelines and other decision-making supports for providers and patients.

Humans↗

PubMed2026

Two Genomes, one Outcome: Stratifying Donor and Recipient Polygenic Risk Score to Improve Kidney Allograft Longevity.

Kidney transplantation outcomes arise from complex interactions among donor organ quality, recipient susceptibility, and immunologic compatibility, yet conventional clinical risk models explain only a modest fraction of outcome variability. Polygenic risk scores (PRS) offer a promising framework to enhance transplant risk assessment by integrating genome-wide genetic information from both donor and recipient into biologically informed models. This narrative review examines the mechanistic basis for PRS application in kidney transplantation and variant clustering approaches that link polygenic signals to specific biological pathways underlying alloimmunity, fibrosis, and metabolic dysfunction. We compare current PRS construction methodologies, highlighting their respective strengths and limitations in transplant cohorts. Transplant PRS are distinguished from single-genome disease models by their capacity to capture dual-genome interactions, simultaneously quantifying inherited donor organ liability and recipient genetic susceptibility within an integrated framework. This dual-genome architecture requires novel risk stratification paradigms in which combined donor-recipient polygenic profiles inform pretransplant decision-making in ways that neither genome alone can achieve. However, current PRS contribute only incremental variance beyond established clinical predictors, and critical limitations persist, including European ancestry bias, small cohort sizes, incomplete replication, and undefined clinical actionability thresholds. We critically evaluate these implementation barriers and outline future directions for integrating dual-genome PRS with clinical, molecular, and environmental data. The longer-term goal is to advance precision kidney transplantation through applications such as donor selection, immunosuppression tailoring, and individualized posttransplant surveillance. Realizing this potential will require validation in adequately powered, ancestry diverse, prospective transplant cohorts.

Journal Article↗

PubMed2026

Development and Validation of a Clinical Polygenic Risk Report in U.S.-Based Health Systems for 8 Cardiovascular Conditions.

BACKGROUND: Polygenic risk scores (PRS) stratify inherited cardiovascular risk, but their path to clinical implementation remains unclear. OBJECTIVES: We aimed to develop and validate integrated PRS for 8 cardiovascular conditions and outline a framework for their clinical reporting. METHODS: We analyzed genotype and clinical data from 245,394 All of Us Research Program participants. Publicly available PRS for 8 traits-coronary artery disease, atrial fibrillation, type 2 diabetes, venous thromboembolism (VTE), thoracic aortic aneurysm (TAA), extreme hypertension, severe hypercholesterolemia, and elevated lipoprotein(a)-were combined using PRSmix, an elastic-net approach. Integrated PRS were externally validated in 53,306 Mass General Brigham Biobank participants using logistic regression, adjusting for age, sex, and ancestry. RESULTS: Of 53,306 genotyped Mass General Brigham Biobank participants (55.6% women, mean age 53 ± 17 years), integrated PRS demonstrated robust discrimination and appropriate calibration across 8 cardiovascular traits. Comparing high genetic risk (top 10% of PRS distribution, or top 20% for rarer TAA and VTE) vs average risk (26th-75th percentiles, or 21st-80th percentiles for TAA and VTE) yielded ORs: coronary artery disease (3.7 [95% CI: 3.4-4.1]), type 2 diabetes (3.1 [95% CI: 2.8-3.3]), atrial fibrillation (3.0 [95% CI: 2.7-3.3]), VTE (1.9 [95% CI: 1.6-2.0]), TAA (1.7 [95% CI: 1.5-1.9]), hypertension (2.1 [95% CI: 1.8-2.3]), hypercholesterolemia (4.1 [95% CI: 3.7-4.5]), and lipoprotein(a) (41.0 [95% CI: 27.0-62.2]). Incorporating integrated PRS into clinical models improved risk classification, while prospective analyses confirmed significant associations with incident cardiovascular outcomes. CONCLUSIONS: Integrated PRS offer an implementable framework for genetic risk reporting, and are now available as a clinically orderable test. Broader prospective validation studies are needed to further establish clinical utility.

Humans↗

PubMed2025

Psychiatric Polygenic Risk Scores and Week-by-Week Symptomatic Status in Youth with Bipolar Disorder: An Exploratory Study.

Introduction: Prior studies have demonstrated that, in both adults and youth, bipolar disorder (BD) is a polygenic illness. However, no studies have examined polygenic risk scores (PRSs) in relation to the longitudinal course of mood symptoms in youth with BD. Methods: This study included 246 youth of European ancestry with BD (7-20 years old at intake) from the Course and Outcome of Bipolar Youth study and Centre for Youth Bipolar Disorder. Mood symptom severity was assessed at intake and, for 168 participants, prospectively for a median of 8.7 years. PRSs for BD, schizophrenia (SCZ), major depressive disorder (MDD), and attention-deficit/hyperactivity disorder (ADHD) were constructed using genome-wide summary statistics from independent adult cohorts. Results: Higher BD-PRS was significantly associated with lower most severe lifetime depression score at intake (β = -0.14, p = 0.03). Higher SCZ-PRS and MDD-PRS were associated with significantly less time spent in euthymia (SCZ-PRS: β = -0.21, p = 0.02; MDD-PRS: β = -0.22, p = 0.01) and more time with any subsyndromal mood symptoms (i.e., any mania, mixed, or depression symptoms; SCZ-PRS: β = 0.15, p = 0.04; MDD-PRS: β = 0.17, p = 0.01) during follow-up. PRSs for BD and ADHD were not significantly associated with any longitudinal mood variable. Conclusions: This exploratory analysis was the first to examine psychiatric PRSs in relation to the prospective course of mood symptoms among youth with BD. Results from the current study can serve to guide future youth BD studies with larger sample sizes on this topic.

Humans↗