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PubMed2025

DiscoDivas: Leveraging genetic ancestry continuum information to interpolate PRS for admixed populations.

The relatively low representation of admixed populations in both discovery and fine-tuning individual-level datasets limits polygenic risk score (PRS) development and equitable clinical translation for admixed populations. Under the assumption that the most informative PRS model for a genetically homogeneous sample varies linearly in an ancestry continuum space, we introduce a Genetic Distance-assisted PRS Combination Pipeline for Diverse Genetic Ancestries (DiscoDivas) to interpolate a harmonized PRS for diverse, especially admixed, genetic ancestries, leveraging multiple PRS models fine-tuned within existing samples, which are mostly of single ancestry, and genetic distance. DiscoDivas treats genetic ancestry as a continuous variable and does not require shifting between different models when calculating PRS for different ancestries. We generated PRS with DiscoDivas and the current conventional method, i.e. fine-tuning multiple GWAS PRS using the matched or similar genetic ancestry samples. DiscoDivas generated a harmonized PRS of the accuracy comparable to or higher than the conventional approach, with the greatest advantage exhibited in admixed individuals.

PRS harmonization↗

PubMed2024

Distinguishing different psychiatric disorders using DDx-PRS.

Despite great progress on methods for case-control polygenic prediction (e.g. schizophrenia vs. control), there remains an unmet need for a method that genetically distinguishes clinically related disorders (e.g. schizophrenia (SCZ) vs. bipolar disorder (BIP) vs. depression (MDD) vs. control); such a method could have important clinical value, especially at disorder onset when differential diagnosis can be challenging. Here, we introduce a method, Differential Diagnosis-Polygenic Risk Score (DDx-PRS), that jointly estimates posterior probabilities of each possible diagnostic category (e.g. SCZ=50%, BIP=25%, MDD=15%, control=10%) by modeling variance/covariance structure across disorders, leveraging case-control polygenic risk scores (PRS) for each disorder (computed using existing methods) and prior clinical probabilities for each diagnostic category. DDx-PRS uses only summary-level training data and does not use tuning data, facilitating implementation in clinical settings. In simulations, DDx-PRS was well-calibrated (whereas a simpler approach that analyzes each disorder marginally was poorly calibrated), and effective in distinguishing each diagnostic category vs. the rest. We then applied DDx-PRS to Psychiatric Genomics Consortium SCZ/BIP/MDD/control data, including summary-level training data from 3 case-control GWAS ( N =41,917-173,140 cases; total N =1,048,683) and held-out test data from different cohorts with equal numbers of each diagnostic category (total N =11,460). DDx-PRS was well-calibrated and well-powered relative to these training sample sizes, attaining AUCs of 0.66 for SCZ vs. rest, 0.64 for BIP vs. rest, 0.59 for MDD vs. rest, and 0.68 for control vs. rest. DDx-PRS produced comparable results to methods that leverage tuning data, confirming that DDx-PRS is an effective method. True diagnosis probabilities in top deciles of predicted diagnosis probabilities were considerably larger than prior baseline probabilities, particularly in projections to larger training sample sizes, implying considerable potential for clinical utility under certain circumstances. In conclusion, DDx-PRS is an effective method for distinguishing clinically related disorders.

Journal Article↗

PubMed2026

Distinguishing different psychiatric disorders using DDx-PRS.

Despite great progress on case-control polygenic prediction, an unmet need remains for a method that genetically distinguishes clinically related disorders (e.g., schizophrenia (SCZ) versus bipolar disorder (BIP) versus major depressive disorder (MDD) versus controls). We introduce differential diagnosis-polygenic risk score (DDx-PRS), which jointly estimates the posterior probabilities of each diagnostic category (e.g., SCZ = 50%, BIP = 25%, MDD = 15%, control = 10%) by modeling variance-covariance structure across disorders, leveraging case-control polygenic risk scores and prior clinical probabilities for each diagnostic category. We applied DDx-PRS to Psychiatric Genomics Consortium SCZ, BIP, MDD and control data, including summary-level training data from three case-control genome-wide association studies (n = 41,917-173,140 cases; total n = 1,048,683) and held-out test data from different cohorts with equal numbers for each diagnostic category (total n = 11,460). DDx-PRS was well calibrated and well powered (consistent with simulations) and produced comparable results to methods that require tuning data. True diagnosis probabilities in the top deciles of predicted diagnosis probabilities were considerably larger than prior baseline probabilities, implying appreciable potential for clinical utility in certain settings.

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↗

PubMed2026

REPLY: Heterogeneous Value of a Multicondition Cardiovascular PRS Panel.

Explore the source record for details and available documents.

Letter↗

PubMed2026

Clinical implementation of polygenic risk scores-updates on ancestry-adjusted PRS and their use in practice.

Explore the source record for details and available documents.

Letter↗

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

Cross-Ancestry and Phenome-Wide Associations of Cancer-Specific Polygenic Risk Scores.

PURPOSE: Genome-wide association studies have identified many common variants associated at low effect sizes with various cancers. Summing the effects of these variants into polygenic risk scores (PRS) can improve cancer risk prediction. However, cross-cancer and cross-phenotype pleiotropic associations of cancer-specific PRS are limited. METHODS: Using logistic regression models, we tested the association of 13 cancer-specific PRS with curated phenotypes representing the same 13 cancers and 340 cancer and cardiometabolic phecodes in 560,287 individuals (114,255 African ancestry [AFR] and 446,032 European ancestry [EUR]) from the Million Veteran Program. Models were stratified by ancestry and used age, principal components, and cancer-specific PRS per standard deviation as independent variables, and correction was applied for multiple comparisons. RESULTS: All 13 cancer-specific PRS were significantly associated with their respective cancers among EUR individuals with odds ratios per standard deviation of PRS (odds ratio [OR]) 1.05-1.70. Among AFR individuals, the effect sizes of the cancer PRS were lower, with OR 1.01-1.48, and cancer-specific PRS were significantly associated with their respective cancers for five of 13 cancers (bladder, breast in female patients, colorectal, prostate, and thyroid). In cancer-cancer pleiotropy studies, only the renal cancer-specific PRS was significantly associated with skin cancer (OR = 1.04, P = 4.5 × 10-06) among EUR individuals. PheWAS demonstrated five positive pleotropic associations with cardiometabolic conditions (thyroid cancer PRS with thyroid goiter, oral cancer PRS with diabetes phenotypes, and hypothyroidism) and two negative associations (oral and lung cancer PRS separately with coronary artery disease). CONCLUSION: Cancer PRS have stronger associations per cancer among EUR versus AFR individuals. In contrast to PRS of other chronic diseases, the majority of cancer-related PRS are highly specific and pleiotropic associations with other cancers and cardiometabolic traits are uncommon.

Female↗

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↗

PubMed2022

Patient and provider perspectives on polygenic risk scores: implications for clinical reporting and utilization.

BACKGROUND: Polygenic risk scores (PRS), which offer information about genomic risk for common diseases, have been proposed for clinical implementation. The ways in which PRS information may influence a patient's health trajectory depend on how both the patient and their primary care provider (PCP) interpret and act on PRS information. We aimed to probe patient and PCP responses to PRS clinical reporting choices METHODS: Qualitative semi-structured interviews of both patients (N=25) and PCPs (N=21) exploring responses to mock PRS clinical reports of two different designs: binary and continuous representations of PRS. RESULTS: Many patients did not understand the numbers representing risk, with high numeracy patients being the exception. However, all the patients still understood a key takeaway that they should ask their PCP about actions to lower their disease risk. PCPs described a diverse range of heuristics they would use to interpret and act on PRS information. Three separate use cases for PRS emerged: to aid in gray-area clinical decision-making, to encourage patients to do what PCPs think patients should be doing anyway (such as exercising regularly), and to identify previously unrecognized high-risk patients. PCPs indicated that receiving "below average risk" information could be both beneficial and potentially harmful, depending on the use case. For "increased risk" patients, PCPs were favorable towards integrating PRS information into their practice, though some would only act in the presence of evidence-based guidelines. PCPs describe the report as more than a way to convey information, viewing it as something to structure the whole interaction with the patient. Both patients and PCPs preferred the continuous over the binary representation of PRS (23/25 and 17/21, respectively). We offer recommendations for the developers of PRS to consider for PRS clinical report design in the light of these patient and PCP viewpoints. CONCLUSIONS: PCPs saw PRS information as a natural extension of their current practice. The most pressing gap for PRS implementation is evidence for clinical utility. Careful clinical report design can help ensure that benefits are realized and harms are minimized.

Clinical Decision-Making↗

PubMed2026

Role of Polygenic Risk Scores in Predicting Cognitive Functioning after Mild Traumatic Brain Injury: A TRACK-TBI Study.

Patients with traumatic brain injury (TBI) and Glasgow Coma Scale scores of 13-15 (historically called mild TBI [mTBI]) commonly experience changes in cognitive functioning, including processing speed, memory, and executive functioning. In a prospective sample (N = 523) of individuals of European descent who had been treated in a U.S. level 1 trauma center for mTBI, we examined the prognostic value of four polygenic risk scores (PRS) for cognitive outcomes at 6-months postinjury. To estimate the impact of mTBI on cognition, primary cognitive outcomes were scaled as z-scores reflecting changes in performance relative to predicted preinjury performance. The PRS examined were previously developed and validated to predict cognition-related outcomes of educational attainment (Education-PRS), intelligence (Intelligence-PRS), and Alzheimer's disease (AD-mild traumatic brain injury (APOE)-PRS and AD + APOE-PRS). Both the Education-PRS and Intelligence-PRS displayed bivariate associations with all four cognitive outcomes (β = 0.19-0.32), whereas neither Alzheimer's disease PRS was significantly associated with any outcome. After controlling for other factors known to predict cognitive outcomes of TBI (e.g., sex, education, mTBI severity defined by a combination of Glasgow Coma Scale scores and the presence/absence of acute intracranial findings on clinical neuroimaging), the Education-PRS and Intelligence-PRS remained independently predictive of verbal episodic memory (β = 0.10-0.16), whereas their associations with processing speed and executive functioning were mostly nonsignificant and were mediated through educational attainment. Looking across primary z-score and secondary raw score outcomes, cognitive outcomes 6 months post-mTBI were good on average, and PRS made small independent contributions to outcome prediction. The mediation model findings may support theories of cognitive reserve, which propose that individuals with stronger preinjury cognitive processing abilities (often estimated by educational history) can better compensate for TBI. Moreover, findings indicate that PRS may contribute modestly to multivariable models predicting cognitive function after TBI.

Humans↗

PubMed2025

Polygenic risk of coronary artery disease for long-term survivors of breast cancer.

BACKGROUND: Cardiovascular disease is a leading cause of death for long-term breast cancer survivors. We evaluated whether a polygenic risk score for coronary artery disease (CAD-PRS) was associated with the risk of incident CAD for survivors of unilateral or contralateral breast cancer. METHODS: The study included 1307 women with breast cancer first diagnosed at younger than 55 years of age who participated in the Women's Environmental Cancer and Radiation Epidemiology Follow-up Study. The CAD-PRS was based on a PRS developed and validated in a separate population. We modeled the association between incident CAD and the CAD-PRS, adjusting for age, CAD risk factors, first (and second) breast cancer treatment, study recruitment phase, and genetic population stratification. We also explored whether the risk of CAD depended on interactions between the CAD-PRS and cardiotoxic cancer treatment. RESULTS: There were 66 incident CAD diagnoses reported at a median of 16 years after breast cancer diagnosis. Participants with CAD-PRS at or above the median had a 2.48-times increased risk of CAD (95% confidence interval [CI] = 1.44 to 4.29) relative to participants with CAD-PRS below the median. Anthracycline-based chemotherapy was associated with increased CAD risk (hazard ratio [HR] = 2.04, 95% CI = 1.04 to 3.98), and the association was not modified by the CAD-PRS. The association between incident CAD and left-sided radiation therapy (RT) was increased for those with CAD-PRS at or above the median (HR = 2.90, 95% CI = 1.26 to 6.68) but not for those with CAD-PRS below the median (HR = 0.96, 95% CI = 0.32 to 2.88). There was evidence of super-additive interaction between the CAD-PRS and left-sided RT (relative excess risk due to interaction = 2.06, 95% CI = 0.05 to 4.06). CONCLUSION: A genome-wide CAD-PRS was associated with nonfatal CAD risk for long-term breast cancer survivors, providing potential utility for personalized cardiovascular care, particularly after RT.

Humans↗

PubMed2025

Robust pleiotropy-decomposed polygenic scores identify distinct contributions to elevated coronary artery disease polygenic risk.

BACKGROUND: Polygenic risk score (PRS) have proved to offer robust risk prediction for coronary artery disease (CAD). However, the global CAD PRS summarizes the joint effects of all the markers in the genome, masking potential genetic heterogeneity that may be important for disease interpretation and targeted interventions. METHODS: Using summary-level data, we identified 43 significant CAD-related traits based on genetic correlations, and further classified them into eight pleiotropy clusters based on their biological functions. We then partitioned the genome into 2,353 near-independent regions. Variants in each region were assigned to the trait most genetically similar to CAD, and then were labeled with the corresponding pleiotropy cluster. We grouped variants without labels into a ninth, non-specific cluster. The Pleiotropy Decomposed (PD) PRSs for each of the nine clusters were calculated using variants assigned to each cluster for 407,903 samples of European ancestry from the UK Biobank (UKBB). RESULTS: We decomposed the CAD PRS into nine PD-PRSs and further stratified individuals with high CAD-PRS into nine subgroups. Each PD-PRS accounted for a higher proportion of the global CAD-PRS within its corresponding subgroup than in the remaining subjects with high CAD-PRS (e.g., 25.2% (0.07) vs. 10.06% (0.07) for lipids-PD-PRS). Additionally, these subgroups showed distinct clinical features. For example, in the lipids-related subgroup, lipoprotein(a) and LDL-cholesterol levels were 67.5% and 18.3% higher, respectively, compared to the remaining high-risk individuals. Furthermore, significant interactions were observed between blood pressure and BP PD-PRS, and between current smoking and respiratory system PD-PRS. CONCLUSION: Our findings suggest that PD-PRSs may reveal substantial genetic and phenotypic heterogeneity among individuals with high CAD-PRS. The unique PD-PRS compositions of each individual can highlight the relative importance of different pleiotropic regions.

Humans↗

PubMed2026

Comparison of Performance of Publicly Available Polygenic Risk Scores to Predict Clinically Actionable Coronary Artery Calcium Scores: The BioHEART-CT Cohort.

AIM: Coronary artery disease (CAD) remains the leading cause of morbidity and mortality globally. Polygenic Risk Scores (PRS) have been trained against major adverse cardiovascular outcomes (MACE) in large cohorts. Few studies have examined the effectiveness of these CAD MACE PRS tools in detecting individuals with subclinical coronary calcification. An association would provide an opportunity for clinical translation and targeting of CT imaging to new patients at risk for subclinical disease. METHODS: An analysis of 53 publicly available CAD PRS tools was completed in participants of the BioHEART-CT Discovery 1000 cohort presenting for clinically referred CT coronary angiography (CCTA). Associations between PRS and two binary CACS outcomes reflecting clinically significant coronary calcification were assessed: a) Absolute CACS (CACS ≥100 Agatston units [AU]; and b) Percentile CACS (CACS ≥75th age-/sex-adjusted percentile). Models were adjusted for genetic principal components, modifiable cardiovascular risk factors, and age/sex (in Absolute CACS). A subgroup analysis was performed using Framingham Risk Score (FRS) at baseline. RESULTS: Among 803 BioHEART-CT Discovery 1000 participants, 487 (60.6%) had any detectable coronary calcium. Most PRS tools demonstrated significant association with CACS outcomes, particularly evident when PRS was modelled as a continuous predictor. For Percentile CACS, 94.3% of PRS tools were significantly associated after full adjustment (median OR per PRS SD 1.41 (IQR 1.23-1.60). Quintile-based analysis revealed that individuals in the Top Quintile PRS had up to 7.99-fold increased odds of Percentile CACS ≥75th compared to those in the Bottom Quintile. Analysis by FRS group revealed positive performance, especially in individuals of Low FRS wherein incorporating a PRS increased pre-test probability from 14% to 26%. CONCLUSION: Whilst most CAD PRS tools have been developed against clinical events, we show their ability to predict clinically relevant coronary calcification. Utility appears strongest in individuals traditionally considered lower risk, presenting an opportunity for clinical translation for improved diagnosis in the primary prevention setting, with the potential to triage individuals into a CACS screening pathway.

coronary artery disease↗

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

Rare variants and survival of patients with idiopathic pulmonary fibrosis: analysis of a multicentre, observational cohort study with independent validation.

BACKGROUND: Rare pathogenic variants in telomere-related genes are associated with poorer clinical outcomes in idiopathic pulmonary fibrosis (IPF). We aimed to assess whether rare qualifying variants in monogenic adult-onset pulmonary fibrosis genes are associated with IPF survival. Using polygenic risk scores (PRS), we also evaluated the influence of common IPF risk variants in patients carrying the qualifying variants. METHODS: We identified qualifying variants in telomere and non-telomere genes using whole-genome sequences from individuals clinically diagnosed with IPF and enrolled in the Pulmonary Fibrosis Foundation Patient Registry (PFFPR), a large multicentre, observational cohort study (March 29, 2016 to June 15, 2018, n=888). We also derived a PRS for IPF (PRS-IPF) from known common sentinel IPF variants. The primary outcome was the association between qualifying variants and survival. The secondary outcome was the association between qualifying variants and PRS-IPF. We used logistic regression models adjusted for sex, age at diagnosis, and principal components of genetic heterogeneity to examine the mutual relationship of qualifying variants and PRS-IPF. The association between qualifying variants and PRS-IPF with survival was tested using Cox proportional hazard models adjusted for baseline confounders. Validation of the results was sought in data from an independent multicentre, prospective, observational cohort study of IPF in the UK (PROFILE, May 17, 2010 to Sept 5, 2017, n=472), and results were meta-analysed under a fixed-effects model. FINDINGS: We included 888 patients from PFFPR and 472 from PROFILE, totalling 1360 participants. In the PFFPR, carriers of qualifying variants in monogenic adult-onset pulmonary fibrosis genes were associated with lower PRS-IPF (odds ratio 1·79 [95% CI 1·15-2·81]; p=0·010) and shorter survival (hazard ratio 1·53 [1·12-2·10]; p=7·33 × 10-3). Individuals with the lowest PRS-IPF also had worse survival (1·61 [1·25-2·07]; p=1·87 × 10-4). These findings were validated in PROFILE and the meta-analysis of the results showed a consistent direction of effect across both cohorts. INTERPRETATION: We found non-additive effects between qualifying variants and common risk variants in IPF survival, suggesting distinct disease subtypes and raising the possibility of using PRS to guide sequencing prioritisation. Assessing the carrier status for qualifying variants and modelling PRS-IPF promises to further contribute to predicting disease progression among patients with IPF. FUNDING: Instituto de Salud Carlos III; Instituto Tecnológico y de Eenergías Renovables; Cabildo Insular de Tenerife; Fundación DISA; National Heart, Lung, and Blood Institute of the US National Institutes of Health; and UK Medical Research Council.

Humans↗

PubMed2025

A multi-ancestry polygenic risk score for Alzheimer disease is associated with cognitive decline, hippocampal atrophy and neuropathological hallmarks in diverse populations.

Alzheimer disease (AD) has a strong genetic basis, yet previously derived polygenic risk scores (PRS) are heavily weighted by the APOE locus and perform inconsistently across diverse ancestries. We developed an APOE-independent multi-ancestry AD PRS using genome-wide association study summary statistics from cohorts in the United States, Europe and East Asia that were applied to European ancestry (EA), African American (AA), Caribbean Hispanic (CH), and East Asian cohorts from the Alzheimer's Disease Genetics Consortium. PRS performance was evaluated in the multi-ancestry Alzheimer's Disease Sequencing Project (ADSP) dataset and validated in several additional multi-ancestry cohorts. The PRS was significantly associated with AD in the ADSP EA, AA, CH, and Native American Hispanic groups with adjusted odds ratios (ORs) between 1.14 and 1.52 per standard deviation of the PRS. PRS performance was validated in the replication cohorts (ORs 1.21-1.65). The PRS was also associated with poorer memory, executive function, and language performance; greater AD-related neuropathological burden (including CERAD, Braak stage, and Thal phase scores); reduced hippocampal volume; lower CSF Aβ42; and elevated total tau and phosphorylated tau (p-tau), with stronger p-tau associations observed in women. Longitudinal analyses revealed that individuals in the highest PRS decile exhibited the steepest cognitive decline, particularly among those who progressed to AD. Our findings demonstrate the utility of an ancestry-aware and APOE-independent PRS for advancing understanding of the genetic basis of AD across diverse populations. Associations observed with early biological and cognitive changes and potential sex-specific differences support the incorporation of a PRS in clinical trials and personalized intervention and prevention strategies.

Journal Article↗

PubMed2025

Development and evaluation of patient-centred polygenic risk score reports for glaucoma screening.

BACKGROUND: Polygenic risk scores (PRS), which provide an individual probabilistic estimate of genetic susceptibility to develop a disease, have shown effective risk stratification for glaucoma onset. However, there is limited best practice evidence for reporting PRS and patient-friendly reports for communicating PRS effectively are lacking. Here we developed patient-centred PRS reports for glaucoma screening based on the literature, and evaluated them with participants using a qualitative research approach. METHODS: We first reviewed existing PRS reports and literature on probabilistic risk communication. This informed the development of a draft glaucoma screening PRS report for a hypothetical high risk individual from the general population. We designed three versions of the report to illustrate risk using a pictograph, a pie chart and a bell curve. We then conducted semi-structured interviews to assess preference of visual risk communication aids, understanding of risk, content, format and structure of the reports. Participants were invited from an existing study, which aims to evaluate the clinical validity of glaucoma PRS among individuals > 50 years from the general population. Numeracy and literacy levels were assessed. RESULTS: We interviewed 12 individuals. The cohort was highly educated (42% university education), all were European and 50% were female. Numeracy (mean 2.1 ± 0.9, range 0 to 3), graph literacy (mean 2.8 ± 0.8, range 0 to 4) and genetic literacy (mean 24.2 ± 6.2, range - 20 to + 46) showed a range of levels. We analysed the reports under three main themes: visual preferences, understanding risk and reports formatting. The visual component was deemed important to understanding risk, with the pictograph being the preferred visual risk representation, followed by the pie chart and the bell curve. Participants expressed preference for absolute risk in understanding risk, along with the written content explaining the results. The importance of follow-up recommendations and time to glaucoma onset were deemed important. Participants expressed varied opinions in the level of information and the colours used, which informed revisions of the report. CONCLUSIONS: Our study revealed preferences for reporting PRS information in the context of glaucoma screening, to support the development of clinical PRS reporting. Further research is needed to assess PRS communication in other groups representative of target populations and with other target audiences (e.g. referring clinicians), and its potential psychosocial impact in the wider community.

Humans↗