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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↗

PubMed2024

The expected polygenic risk score (ePRS) framework: an equitable metric for quantifying polygenetic risk via modeling of ancestral makeup.

Polygenic risk scores (PRSs) depend on genetic ancestry due to differences in allele frequencies between ancestral populations. This leads to implementation challenges in diverse populations. We propose a framework to calibrate PRS based on ancestral makeup. We define a metric called "expected PRS" (ePRS), the expected value of a PRS based on one's global or local admixture patterns. We further define the "residual PRS" (rPRS), measuring the deviation of the PRS from the ePRS. Simulation studies confirm that it suffices to adjust for ePRS to obtain nearly unbiased estimates of the PRS-outcome association without further adjusting for PCs. Using the TOPMed dataset, the estimated effect size of the rPRS adjusting for the ePRS is similar to the estimated effect of the PRS adjusting for genetic PCs. Similarly, we applied the ePRS framework to six cardiovascular-related traits in the All of Us dataset, and the results are consistent with those from the TOPMed analysis. The ePRS framework can protect from population stratification in association analysis and provide an equitable strategy to quantify genetic risk across diverse populations.

Journal Article↗

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↗

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

Polygenic liability for anxiety in association with comorbid anxiety in multiple sclerosis.

OBJECTIVE: Comorbid anxiety occurs often in MS and is associated with disability progression. Polygenic scores offer a possible means of anxiety risk prediction but often have not been validated outside the original discovery population. We aimed to investigate the association between the Generalized Anxiety Disorder 2-item scale polygenic score with anxiety in MS. METHODS: Using a case-control design, participants from Canadian, UK Biobank, and United States cohorts were grouped into cases (MS/comorbid anxiety) or controls (MS/no anxiety, anxiety/no immune disease or healthy). We used multiple anxiety measures: current symptoms, lifetime interview-diagnosed, and lifetime self-report physician-diagnosed. The polygenic score was computed for current anxiety symptoms using summary statistics from a previous genome-wide association study and was tested using regression. RESULTS: A total of 71,343 individuals of European genetic ancestry were used: Canada (n = 334; 212 MS), UK Biobank (n = 70,431; 1,390 MS), and the USA (n = 578 MS). Meta-analyses identified that in MS, each 1-SD increase in the polygenic score was associated with ~50% increased odds of comorbid moderate anxious symptoms compared to those with less than moderate anxious symptoms (OR: 1.47, 95% CI: 1.09-1.99). We found a similar direction of effects in the other measures. MS had a similar anxiety genetic burden compared to people with anxiety as the index disease. INTERPRETATION: Higher genetic burden for anxiety was associated with significantly increased odds of moderate anxious symptoms in MS of European genetic ancestry which did not differ from those with anxiety and no comorbid immune disease. This study suggests a genetic basis for anxiety in MS.

Humans↗

PubMed2025

Stratifying Lung Adenocarcinoma Risk with Multi-ancestry Polygenic Risk Scores in East Asian Never-Smokers.

BACKGROUND: Lung adenocarcinoma (LUAD) in never-smokers is a major public health burden, especially among East Asian women. Polygenic risk scores (PRSs) are promising for risk stratification but are primarily developed in European-ancestry populations. We aimed to develop and validate single- and multi-ancestry PRSs for East Asian never-smokers to improve LUAD risk prediction. METHODS: PRSs were developed using genome-wide association study summary statistics from East Asian (8,002 cases; 20,782 controls) and European (2,058 cases; 5,575 controls) populations. Single-ancestry models included PRS-25, PRS-CT, and LDpred2; multi-ancestry models included LDpred2+PRS-EUR128, PRS-CSx, and CT-SLEB. Performance was evaluated in independent East Asian data from the Female Lung Cancer Consortium (FLCCA) and externally validated in the Nanjing Lung Cancer Cohort (NJLCC). We assessed predictive accuracy via AUC, with 10-year and (age 30-80) absolute risks estimates. RESULTS: The best multi-ancestry PRS, using East Asian and European data via CT-SLEB (clumping and thresholding, super learning, empirical Bayes), outperformed the best East Asian-only PRS (LDpred2; AUC=0.629, 95% CI:0.618,0.641), achieving an AUC of 0.640 (95% CI:0.629,0.653) and odds ratio of 1.71 (95% CI:1.61,1.82) per SD increase. NJLCC Validation confirmed robust performance (AUC =0.649, 95% CI: 0.623, 0.676). The top 20% PRS group had a 3.92-fold higher LUAD risk than the bottom 20%. Further, the top 5% PRS group reached a 6.69% lifetime absolute risk. Notably, this group reached the average population 10-year LUAD risk at age 50 (0.42%) by age 41, nine years earlier. CONCLUSIONS: Multi-ancestry PRS approaches enhance LUAD risk stratification in East Asian never-smokers, with consistent external validation, suggesting future clinical utility.

East Asian never smokers↗

PubMed2025

Intersectionality in a sociogenomic world: How do race, disability, socioeconomic status, and polygenic prediction interact to affect perceptions of educational trajectories?

PURPOSE: Education is important for lifelong skills and economic growth; however, student placement decisions may be shaped by social biases. As genomic information captured via polygenic scores becomes more available, it may also inform student placement decisions. We assessed the intersectional effects of polygenic scores, race, disability, and socioeconomic status on US adults' views of educational trajectories using an online experimental survey design. METHODS: A total of 1367 US adults were randomized to one of 16 conditions and prompted to read a short vignette about a boy named Michael, also depicted in an image. Each condition varied Michael's race (Black/White), disability (wheelchair user/no), socioeconomic status (high/low), and polygenic score (high/low) for educational attainment (EA-PGS). After reading the vignette, the respondents were asked to answer multichoice questions about Michael's immediate and long-term educational trajectories. RESULTS: Variation in Michael's EA-PGS strongly influenced participants' expectations regarding (1) the most appropriate immediate educational program for Michael (ie, general, special, or gifted education), (2) whether he would graduate high school, and, if so, (3) the highest educational degree he would complete in his lifetime (associate, bachelor, master, or PhD). Across these responses, high EA-PGS was associated with more socially desirable outcomes, whereas the opposite was true for low EA-PGS. Depicting Michael in a wheelchair significantly influenced respondents' expectations that his most appropriate immediate educational trajectory would be special. There were significant interactions between Michael's race, disability, socioeconomic status, and the EA-PGS. CONCLUSION: Information about children's EA-PGS may affect their views about their immediate and long-term educational trajectories. The negative effects of low EA-PGS were comparable to those of high EA-PGS. The EA-PGS may be interpreted in ways that compound the existing stereotypes related to a child's race, disability, and socioeconomic status.

Humans↗

PubMed2026

Polygenic risk scores in major depressive disorder: A systematic review across diagnostic, treatment, course/severity, and subtype domains.

BACKGROUND: Major depressive disorder (MDD) is heterogeneous across diagnostic, treatment-related, course/severity, and subtype domains. Polygenic risk score (PRS) studies have examined these domains, but differences in PRS sources, samples, methods, and endpoint definitions have fragmented the evidence. We synthesised findings and examined potential contributors to heterogeneity. METHODS: PubMed/MEDLINE, Embase, PsycINFO, and Web of Science were searched for studies published from January 2016 through 25 November 2025. Result records were synthesised using SWiM, and certainty was assessed with an adapted GRADE framework. RESULTS: Sixty studies contributed 493 retained records; 450 were descriptively classified as positive, null, or reverse, although records were not independent. Positive findings accounted for 44/56 diagnostic, 61/273 treatment-related, 64/100 course/severity, and 14/21 subtype records. For MDD/depression-derived PRSs and case-control MDD status, all 10 contributing studies showed higher liability in cases (exploratory exact sign test p = 0.002; FDR q = 0.004). The same PRS group showed positive findings for overall depressive symptom severity (14/18), although the study-level test was imprecise (5/5 studies; p = 0.063). Pharmacological response/remission findings for these PRSs were mostly null or directionally mixed (10 positive, 18 null, and 9 reverse). Treatment-resistant depression (TRD) findings differed by operational definition. Atypical and psychotic subtype signals arose mainly from single-study PRS and endpoint contrasts. CONCLUSIONS: PRS evidence was clearest for MDD diagnostic status and showed a tentative pattern for overall symptom burden. Treatment and subtype findings were less consistent or less replicated. Larger, ancestrally diverse studies with standardised endpoints and transparent PRS methods are needed.

Humans↗

PubMed2026

A multiancestry polygenic risk score for Alzheimer's disease is associated with cognitive decline and neuropathological hallmarks in diverse populations.

Previously derived polygenic risk scores (PRSs) for Alzheimer's disease (AD) perform inconsistently across diverse ancestries. We developed an APOE-independent multiancestry AD PRS using genome-wide association study summary statistics applied to European ancestry, African American, Caribbean Hispanic and East Asian cohorts. PRS performance was evaluated in a large independent multiancestry dataset and validated in several additional multiancestry cohorts. The PRS was significantly associated with AD in European ancestry, African American, Caribbean Hispanic and Native American Hispanic groups with adjusted odds ratios between 1.14 and 1.52 per PRS standard deviation. PRS performance was validated in the replication cohorts (odds ratios: 1.21-1.65). The PRS was also associated with poorer memory, executive function and language performance, greater AD-related neuropathological burden, reduced hippocampal volume, lower cerebrospinal fluid amyloid-β42 and elevated total tau and phosphorylated tau, with stronger phosphorylated tau associations observed in women. Our findings support the value of ancestry-aware PRSs as a component of broader multimodal risk stratification frameworks.

Aged↗

PubMed2025

Evaluating the causal effect of mitochondrial dysfunction on Alzheimer's and Parkinson's disease using Polygenic Risk Scores and Mendelian Randomization.

INTRODUCTION: Mitochondrial DNA copy number (mtDNAcn), a measure of mitochondrial genomes per nucleated cell, has an unclear causal relationship with AD and PD. We integrate genetic correlation, Polygenic Risk Scores (PRS), and Mendelian Randomization (MR) to assess whether mtDNAcn influences the risk of AD and PD, and evaluate how study-specific factors in mtDNAcn genome-wide association studies (GWAS) may distort these causal estimates. METHODS: Using GWAS of four mtDNAcn measures, AD, AD/dementia, and PD, we evaluated genetic correlations, generated ancestry-normalized PRS in the AD Genetics Consortium (N=27,383), and applied MR methods including Latent Heritable Confounder MR (LHC-MR). RESULTS: Across the four mtDNAcn GWAS, only one was consistently associated with AD/dementia and PD, with genetic correlations and PRS analysis showing negative correlations and MR indicating that higher mtDNAcn reduced AD/dementia and PD risk. DISCUSSION: Higher blood-based mtDNAcn was causally associated with reduced risk of AD/dementia and PD, with limited evidence to suggest a bidirectional effect.

Alzheimer’s disease↗

PubMed2026

Polygenic Risk Scores for Incident Dementia in the Multi-Ethnic Study of Atherosclerosis.

Over 75 Alzheimer's disease (AD) and dementia-associated variants have been identified through genome-wide association studies, but the utility of polygenic risk scores (PRS) for predicting AD and dementia in diverse and admixed populations remains unclear. We compared how PRS approaches differing in p-value thresholds, variant weights, and source ancestry perform in predicting dementia in 6338 African American, Chinese, Hispanic, and White individuals from the Multi-Ethnic Study of Atherosclerosis. We tested clumping and thresholding (C+T) methods with varying parameters against Bayesian approaches (PRS-CS, PRS-CSx). We compared the ability of each method to predict incident dementia in all participants and in groups stratified by self-reported race/ethnicity. We additionally analyzed performance across groups stratified by estimated proportion of non-Finnish European (NFE)-like ancestry. Including more variants does not improve performance. We found comparable associations between dementia and PRS when comparing a C+T method with only 15 SNPs and PRS derived from Bayesian models that include > 800,000 SNPs (HR5e-08 = 1.18, 95% CI: 1.08-1.28; HRCSx = 1.17, 95% CI: 1.07-1.27). The p < 5e-08 C+T method was more strongly associated with incident dementia in populations genetically dissimilar from the source data (HRlowNFE_5e-08 = 1.27, 95% CI: 1.08-1.50; HRlowNFE_CSx = 1.12, 95% CI: 0.94-1.33). More selective PRS models using genome-wide significant SNPs may be preferable for dementia prediction in diverse populations.

Aged↗

PubMed2026

Implementing a Multi-Ancestry Polygenic Risk Score for Coronary Heart Disease in a Diverse Cohort.

PURPOSE: We describe a prospective cohort study (NCT05277116) conducted in phase IV of the electronic MEdical Records and GEnomics (eMERGE) Network to implement a multi-ancestry polygenic risk score for coronary heart disease (PRSCHD: PGS004696) and assess outcomes after return of results (RoR). METHODS: PRSCHD was considered alongside family history (FamHxCHD), monogenic risk from familial hypercholesterolemia (FH), and clinical risk factors, to return CHD risk as part of a Genome Informed Risk Assessment (GIRA) report. Participants with high PRSCHD (top 5th percentile) or FH received their results from study personnel, while participants with FamHxCHD were informed by mail/email. Results were placed in the electronic health record and communicated to the primary care provider. The primary outcome of initiation/intensification of lipid lowering therapy within 12 months after RoR is compared between participants with PRSCHD ≥95th percentile and those with PRSCHD 90th-94th percentile, using a regression discontinuity design. Secondary outcomes include ordering of screening tests, a new CHD diagnosis, and lifestyle changes. RESULTS: By April 2025, 20,421 adults were enrolled: mean age 50±15 years (range 18-75 years), 68% female, 50% belonging to health disparity groups, and 40% non-White by self-report. Prevalence of CHD, FamHxCHD, high PRSCHD and FH was 4.0%, 10.2%, 4.3% and 0.7%, respectively; 14.3% had at least one of the three CHD genetic risk factors and CHD risk estimates were highest in those who self-reported as Black. CONCLUSION: The prevalence of increased genetic risk for CHD was high and at least one of the three genetic risk factors for CHD was present in 14.2% of the cohort. Analyses are underway to assess outcomes after PRSCHD implementation in the context of FamHxCHD, FH, and clinical risk, across the age spectrum in a diverse cohort.

PRS↗

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

Integrating Imaging-Derived Clinical Endotypes with Plasma Proteomics and External Polygenic Risk Scores Enhances Coronary Microvascular Disease Risk Prediction.

Coronary microvascular disease (CMVD) is an underdiagnosed but significant contributor to the burden of ischemic heart disease, characterized by angina and myocardial infarction. The development of risk prediction models such as polygenic risk scores (PRS) for CMVD has been limited by a lack of large-scale genome-wide association studies (GWAS). However, there is significant overlap between CMVD and enrollment criteria for coronary artery disease (CAD) GWAS. In this study, we developed CMVD PRS models by selecting variants identified in a CMVD GWAS and applying weights from an external CAD GWAS, using CMVD-associated loci as proxies for the genetic risk. We integrated plasma proteomics, clinical measures from perfusion PET imaging, and PRS to evaluate their contributions to CMVD risk prediction in comprehensive machine and deep learning models. We then developed a novel unsupervised endotyping framework for CMVD from perfusion PET-derived myocardial blood flow data, revealing distinct patient subgroups beyond traditional case-control definitions. This imaging-based stratification substantially improved classification performance alongside plasma proteomics and PRS, achieving AUROCs between 0.65 and 0.73 per class, significantly outperforming binary classifiers and existing clinical models, highlighting the potential of this stratification approach to enable more precise and personalized diagnosis by capturing the underlying heterogeneity of CMVD. This work represents the first application of imaging-based endotyping and the integration of genetic and proteomic data for CMVD risk prediction, establishing a framework for multimodal modeling in complex diseases.

Cardiovascular Disease↗

PubMed2025

Associations Between Polygenic Risk Score for Blood Pressure and Risk of Hypertension in Northeast Asian Individuals.

BACKGROUND: Data on associations between genetic predisposition to high blood pressure (BP) and hypertension and its complications in non-European populations are limited. The current study investigated associations between polygenic risk scores (PRSs) for BP and risks of hypertension, cardiovascular disease, and chronic kidney disease in Northeast Asian populations. METHODS: A genome-wide association study of systolic BP (SBP) and diastolic BP (DBP) was conducted using data from the KoGES (Korean Genome and Epidemiology Study). Results were meta-analyzed using summary statistics from Biobank Japan to construct PRSs. RESULTS: Compared with a PRS in the lowest 5 percentiles, a PRS in the highest 5 percentiles was associated with an increased risk of hypertension (hazard ratio [HR], 2.44 [95% CI, 1.67-3.56] for PRS for SBP; and HR, 1.77 [95% CI, 1.20-2.62] for PRS for DBP) and earlier onset of hypertension (by a median of 8.5 years for PRS for SBP and 8.0 years for PRS for DBP). These associations remained significant when continuous PRS was analyzed. The genetic risk of hypertension incidence was attenuated by moderate to vigorous physical activity. Adding the PRS for BP to the clinical risk factors improved the predictive value for hypertension (both area under the curve values, 0.787 [95% CI, 0.771-0.803]; P=0.063 for PRS for SBP and [95% CI, 0.771-0.804]; P=0.031 for PRS for DBP). However, neither PRS for SBP nor PRS for DBP was associated with the incidence of cardiovascular or chronic kidney disease. CONCLUSIONS: The PRS for BP was associated with a higher risk of incident hypertension and earlier-onset hypertension in a Northeast Asian population. PRS may facilitate early identification and targeted management of individuals at high risk of developing hypertension.

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↗

PubMed2025

Psychological and emotional impacts of communicating breast cancer risk using multifactorial assessment with polygenic risk score: Findings from PERSPECTIVE I&I.

PURPOSE: To examine the psychological and emotional outcomes of personalized breast cancer risk communication up to 1 year after disclosure in a risk-stratified breast screening preimplementation study (Personalized Risk Assessment for Prevention and Early Detection of Breast Cancer: Integration and Implementation). METHODS: Among 3753 females aged 40 to 69, unaffected by breast cancer, with a prior mammogram, and who underwent multifactorial risk assessment to estimate their 10-year breast cancer risk, 2734 completed follow-up questionnaires up to 1 year after risk communication: 78.5% were at average risk, 16.5% at higher than average risk, and 5.0% at high risk. The impact of risk communication on breast cancer worry and psychological distress and factors associated with decisional regret were examined. RESULTS: Breast cancer worry and psychological distress scores remained low after risk communication and at 1 year follow-up. Up to 1 year after disclosure, small significant differences in breast cancer worry were observed between risk levels. Decisional regret was very low 1 year after risk communication. Lower levels of decisional regret were significantly associated with some factors, including higher satisfaction with the information received. CONCLUSION: This study suggests that personalized breast cancer risk communication has low negative psychological and emotional effects and highlights the importance of the information received for implementing this approach at population level.

Humans↗

PubMed2025

Identification of plasma proteomic markers underlying polygenic risk of type 2 diabetes and related comorbidities.

Genomics can provide insight into the etiology of type 2 diabetes and its comorbidities, but assigning functionality to non-coding variants remains challenging. Polygenic scores, which aggregate variant effects, can uncover mechanisms when paired with molecular data. Here, we test polygenic scores for type 2 diabetes and cardiometabolic comorbidities for associations with 2,922 circulating proteins in the UK Biobank. The genome-wide type 2 diabetes polygenic score associates with 617 proteins, of which 75% also associate with another cardiometabolic score. Partitioned type 2 diabetes scores, which capture distinct disease biology, associate with 342 proteins (20% unique). In this work, we identify key pathways (e.g., complement cascade), potential therapeutic targets (e.g., FAM3D in type 2 diabetes), and biomarkers of diabetic comorbidities (e.g., EFEMP1 and IGFBP2) through causal inference, pathway enrichment, and Cox regression of clinical trial outcomes. Our results are available via an interactive portal ( https://public.cgr.astrazeneca.com/t2d-pgs/v1/ ).

Humans↗