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At least 19 recordsLinked to original sources

PubMed2026

PGR expression as a pharmacogenomic companion biomarker to GENE70-derived genomic risk in ER-positive/HER2-negative breast cancer.

BACKGROUND: The biology of the estrogen receptor-positive (ER+) and human epidermal growth factor receptor 2-negative (HER2-) breast cancers is heterogeneous even when they are categorized by their risk via genomics. Transcriptomic PGR expression reflects endocrine pathway activity and may provide complementary biological information within established GENE70-derived genomic-risk categories. Whether this molecular marker improves the biological interpretation of genomic-risk stratification beyond conventional clinicopathological assessment remains uncertain. OBJECTIVES: The aim of this study was to determine whether transcriptomic PGR expression provides complementary biological and prognostic information within reconstructed GENE70-derived genomic-risk categories and refines the characterization of endocrine-related tumour biology in ER-positive/HER2-negative breast cancer. METHODS: This study analysed publicly available transcriptomic and clinical data from three cohorts: METABRIC (discovery cohort), GSE96058/SCAN-B cohort (validation cohort) and TCGA-BRCA cohort (molecular validation cohort). The GENE70-derived genomic-risk score was reconstructed for each cohort using matched genes. Cox regression, Kaplan-Meier analysis and subgroup comparisons were used to assess relationships between PGR expression, clinicopathologic variables, molecular features and survival outcomes. RESULTS: Across the three independent cohorts, low transcriptomic PGR expression was consistently associated with higher GENE70-derived genomic risk, increased MKI67 expression, reduced ESR1 expression and enrichment of the Luminal B subtype. Survival findings differed between cohorts. In the discovery METABRIC cohort, transcriptomic PGR expression showed heterogeneous associations with survival, particularly within GENE70-derived high-risk subgroups, whereas the external GSE96058/SCAN-B validation cohort demonstrated consistent associations between low PGR expression and poorer overall survival in both the overall ER-positive/HER2-negative population and GENE70-derived high-risk subgroups. CONCLUSION: These findings suggest that transcriptomic PGR provides complementary biological and prognostic information within GENE70-derived genomic-risk categories. However, because treatment response was not evaluated in the present study, the findings should not be interpreted as evidence of predictive or pharmacogenomic utility and prospective studies incorporating treatment-response analyses are required before such applications can be established.

Humans↗

PubMed2026

Bridging Ancestry Gaps in Genomic Risk Prediction with Tabular Foundation Models.

MOTIVATION: Models deployed for genomic prediction of diseases perform unevenly across populations, limiting clinical utility. Two factors drive this limitation: large imbalances in sample availability across ancestry groups and non-stationarity of genotype-phenotype effect sizes across the ancestry continuum. While tabular foundation models with in-context learning (ICL) have shown strong sample efficiency in other domains, their effectiveness for genotype-to-phenotype prediction and their robustness to ancestry-driven effect heterogeneity remain unclear. RESULTS: Using large, ancestrally diverse biobank data, we show that ICL-capable tabular foundation models reduce performance degradation in under-sampled ancestry groups compared to conventional supervised approaches. However, we find that prevailing models trained on existing synthetic tabular tasks fail when allele effect sizes vary across ancestry space. Treating genetic ancestry as a continuous variable, we introduce an instruction-tuning framework that exposes models to synthetic tasks with ancestry-dependent non-stationary effects. Instruction-tuned models achieve improved and more stable predictive performance across the genetic ancestry continuum, including for individuals distant from in-context exemplars in ancestry space. AVAILABILITY AND IMPLEMENTATION: All code for instruction-tuning models, synthetic task generation, data wrangling, and model evaluation, is publicly available at https://github.com/ai4pm/Bridging-Ancestry-Gaps-in-Genomic-Risk-Prediction-with-Tabular-Foundation-Models. The final instruction-tuned model (ICL-NS-G2P-proto) is also released in this repository. Detailed documentation is provided, including environment setup instructions and guidelines for running various parts. The instruction-tuning task datasets are available at https://zenodo.org/records/18309187.

Ancestry Continuum↗

PubMed2026

Bridging ancestry gaps in genomic risk prediction with tabular foundation models.

Humans↗

PubMed2026

Genomic risk profiling in advanced maternal age: a Tamil Nadu prenatal study.

BACKGROUND: Advanced maternal age (AMA; > = 35 years) is associated with increased fetal chromosomal risk and is an important indication for invasive prenatal diagnosis. This study evaluates karyotyping and chromosomal microarray analysis (CMA) findings among AMA pregnancies in Tamil Nadu, India. METHODS: In this prospective observational study, 2,200 pregnant women aged ≥35 years who underwent amniocentesis between July 2020 and June 2021 were enrolled. Conventional karyotyping was performed in all cases. CMA was performed as a reflex or complementary test when predefined clinical or cytogenetic criteria were present, including ultrasound abnormalities, high-risk screening/NIPT results, abnormal or uncertain karyotype findings, prior adverse pregnancy history suggestive of genetic etiology, parental chromosomal abnormalities, or patient request after counseling. RESULTS: Numerical chromosomal abnormalities were detected in 76/2200 cases (3.5%), and structural abnormalities were detected in 9/2200 cases (0.4%). The total abnormal cytogenetic yield was therefore 85/2200 cases (3.9%) when numerical and structural abnormalities were considered together. Age-stratified analysis showed an increasing trend in chromosomal abnormalities with advancing maternal age, reaching 10.4% in women aged > = 43 years. Cases with additional clinical indications showed higher abnormality rates than simple AMA. CMA was performed in selected cases and contributed to characterization of clinically relevant genomic abnormalities, supporting its role in indicated high-risk AMA pregnancies. CONCLUSION: The Tamil Nadu cohort provides regional evidence on age-stratified cytogenetic risk in AMA pregnancies and supports the use of clearly defined criteria for integrating CMA with conventional karyotyping in prenatal diagnosis.

India↗

PubMed2025

The Role of Genomic-Informed Risk Assessments in Predicting Dementia Outcomes.

INTRODUCTION: By integrating genetic and clinical risk factors into genomic-informed dementia risk reports, healthcare providers can offer patients detailed risk profiles to facilitate understanding of individual risk and support the implementation of personalized strategies for promoting brain health. METHODS: We constructed an additive score comprising the modified Cardiovascular Risk Factors, Aging, and Incidence of Dementia Risk Score (mCAIDE), family history of dementia, APOE genotype, and an AD polygenic risk score in NACC and ADNI, and assessed its association with progression to all-cause dementia. RESULTS: 81% of participants had at least one high-risk indicator for dementia, with each additional risk indicator linked to a 34% increase in the hazard of dementia onset. DISCUSSION: We found that most participants in memory and aging clinics had at least one high-risk indicator for dementia. Furthermore, we observed a dose-response relationship where a greater number of risk indicators was associated with an increased risk of incident dementia.

dementia risk scores↗

PubMed2026

Tumour-infiltrating lymphocytes differ across MammaPrint® classifications in breast cancer.

MammaPrint® refines risk stratification in early oestrogen receptor-positive, HER2-negative breast cancer, evolving from a binary to a four-tier classification (UltraLow-Risk, Low-Risk, High-Risk 1, and High-Risk 2). The relationship between routine histopathological features, immune infiltration, and genomic risk within this framework remains incompletely characterized in luminal disease. We retrospectively analysed 492 luminal breast carcinomas with available MammaPrint® results. Clinicopathological variables (including histological subtype, grade, Ki-67, hormone receptor expression, lymphovascular invasion (LVI), and HER2-low status) were recorded. Stromal tumour-infiltrating lymphocytes (TILs) were quantified according to the criteria of Salgado et al. and spatially categorized as immune-deserted, stromal-restricted, immune-excluded, or inflamed patterns. CD4 and CD8 infiltration was assessed by immunohistochemistry on tissue microarrays. Associations with binary and four-tier MammaPrint® categories were examined using multivariable models. High-Risk tumours (41%) were enriched for increased grade, Ki-67, and LVI and lower PR expression. In High-Risk tumours, inflamed spatial patterns were more frequent and median TIL levels were significantly higher compared with Low-Risk tumours (15% vs 5%, P < 0.001). CD4 and CD8 infiltration increased with genomic risk, and CD4 retained a modest but statistically significant association after adjustment for conventional pathological variables. In the four-tier model, UltraLow-Risk/Low-Risk tumours showed minimal TILs and were enriched for invasive lobular carcinoma, whereas High-Risk 1/High-Risk 2 tumours displayed progressively higher proliferative and immune features. No association was observed between HER2-low status and genomic risk. Immune infiltration parallels proliferative and genomic risk gradients in luminal breast cancer. These findings indicate that immune descriptors align with the genomic risk continuum, although their independent prognostic contribution beyond established genomic assays requires further evaluation.

Humans↗

PubMed2026

Beyond the clinic: a community-embedded, multidomain framework for early detection of glaucoma.

Glaucoma remains one of the leading causes of acquired irreversible blindness worldwide, with normal-tension glaucoma representing the dominant subtype in Japan and several East Asian populations. The insidious, asymptomatic progression of this condition, combined with the demonstrated inadequacy of intraocular pressure alone as a screening criterion, creates a critical gap between disease burden and case detection. Population-based epidemiological studies consistently reveal that the majority of individuals with glaucoma are undiagnosed. Two responses have been suggested: incorporation of retinal imaging into annual health checkups, which warrants formal prospective evaluation, and characterization of individuals at higher risk - integrating genomic risk, oxidative stress biomarkers, systemic lifestyle factors, and ocular blood flow dynamics - which may help identify those in whom damage is most likely to occur. The principal contribution of this Perspective is therefore the implementation model rather than the individual screening components. We introduce the Living Lab ('neighborhood health lab'), a community co-creation platform established under the Japan Science and Technology Agency COI-NEXT 'Vision to Connect' hub at Tohoku University, as a scalable model for operationalizing this framework. Embedded within commercial retail environments, the Living Lab integrates non-invasive screening, longitudinal health data collection, and evidence-based health product development-exemplified by the Ronbun Recipe® concept-within a stakeholder-aligned ecosystem encompassing citizens, researchers, industry, and municipal authorities. Conceived as a platform for well-being rather than as a disease-specific screening service, it engages individuals who are asymptomatic, undiagnosed, and outside existing screening pathways, and who would not otherwise be assessed at all.

Humans↗

PubMed2026

Effects of short-course preoperative endocrine therapy on tumour morphology and immunohistochemical profile in oestrogen receptor-positive, HER2-negative breast cancer.

AIMS: Short-term preoperative endocrine therapy (ET) is increasingly used in oestrogen receptor (ER)-positive, HER2-negative breast cancer as a functional test of endocrine sensitivity. We aimed to characterise histomorphological and immunophenotypic changes following preoperative ET and to identify predictors of endocrine response, defined as post-treatment Ki67 ≤ 10%. METHODS AND RESULTS: In this retrospective single-centre study, 180 patients treated with short-course preoperative ET (median duration 29 days) were compared with 151 patients undergoing primary surgery without ET. Paired biopsy and resection specimens were assessed for histological features, stromal proportion, stromal tumour-infiltrating lymphocytes (strTILs) and expression of ER, progesterone receptor (PR), HER2 and Ki67. Genomic risk was determined using the MammaPrint assay. Preoperative ET was associated with a significant reduction in tumour proliferation, with 73.9% of cases showing post-treatment Ki67 ≤ 10% compared with none in controls (P < 0.001). Histological grade decreased in 36.7% of ET-treated tumours versus 7.9% of controls (P < 0.001), predominantly reflecting reduced mitotic activity. ER expression remained stable, whereas PR expression decreased more frequently following ET (P < 0.001) and was independently associated with Ki67-defined response. HER2-low status was more frequently observed after ET (P < 0.001), but HER2 expression and microenvironmental parameters, including strTILs, were not associated with response. High genomic risk was independently associated with a lower likelihood of achieving post-treatment Ki67 ≤ 10% (P < 0.001). CONCLUSIONS: Short-course preoperative ET induces rapid and reproducible morphological and immunophenotypic changes in ER-positive, HER2-negative breast cancer. Ki67-defined response is associated with genomic risk and PR expression, whereas microenvironmental features appear to have limited predictive value.

Humans↗

PubMed2026

Development and pilot testing of a prostate cancer polygenic risk report.

BACKGROUND: Polygenic risk scores (PRS) are increasingly being incorporated into clinical care, yet optimal strategies for communicating PRS results to patients and clinicians remain undefined. Effective report design is critical to ensure comprehension and appropriate use, particularly for complex conditions such as prostate cancer where screening decisions are nuanced. We developed and pilot tested patient-facing materials to communicate integrated polygenic and monogenic risk for prostate cancer in the context of a randomized clinical trial. METHODS: We designed a summary report and accompanying Frequently Asked Questions (FAQ) page to communicate prostate cancer genetic risk within the Prostate Cancer, Genetic Risk, and Equitable Screening Study (ProGRESS). Materials were developed through an iterative, multidisciplinary process informed by existing literature on genomic risk communication. We conducted semi-structured interviews with a national sample of eight men eligible for prostate cancer screening to evaluate comprehension, interpretation of visual elements, perceived usefulness, and preferences for improvement. Interviews were transcribed and analyzed using reflexive thematic analysis. RESULTS: Participants generally found the summary report and FAQ page understandable and visually engaging. Graphical displays of absolute risk, particularly pictograph arrays, facilitated comprehension and helped contextualize risk. Visual cues such as color and bold formatting effectively directed attention to key information, with red coloring perceived as particularly salient for high-risk results. In contrast, more complex visualizations, including bell curves and incidence curves, were frequently misunderstood or not interpreted as intended. Participants expressed a desire for clearer guidance regarding next steps and additional accessible information, suggesting supplementary resources such as hyperlinks or QR codes. Concerns about readability included small font size and high text density. CONCLUSIONS: In this qualitative pilot study, patient-facing materials for communicating prostate cancer PRS were generally well received, with specific design features such as simple visualizations and clear formatting enhancing understanding. Findings highlight the importance of intuitive risk displays and actionable guidance in PRS reporting. These results provide practical insights to inform the design of genomic risk reports as PRS-based prostate cancer screening approaches move toward clinical implementation. TRIAL REGISTRATION: ClinicalTrials.gov NCT05926102; date of registry: July 3, 2023.

Aged↗

PubMed2026

Genomic Profiling, Risk Stratification, and Post-Transformation Treatment Outcomes in Patients with Transformed Small-Cell Lung Cancer: A Multicenter Analysis.

BACKGROUND: Transformed small-cell lung cancer (T-SCLC) is an increasingly recognized resistance mechanism in EGFR-mutant lung adenocarcinoma. This study aimed to identify early predictors of histologic transformation and evaluate post-transformation treatment outcomes. METHODS: We retrospectively collected 163 T-SCLC patients from five Chinese centers. Next-generation sequencing was performed on 60 EGFR-mutant patients, including 47 paired primary-transformed samples. Integrated genomic and clinical analyses were conducted to delineate molecular features and survival outcomes. RESULTS: Among 150 EGFR-mutant patients, the median time to SCLC transformation was 25.8 months and median post-transformation overall survival (OS) was 14.2 months. Clinical and survival data for the 13 EGFR wild-type patients are reported descriptively given the limited sample size. Among 108 treatment-evaluable patients, first-line EGFR-TKI plus chemotherapy, chemotherapy alone, and immune checkpoint inhibitors (ICIs) plus chemotherapy yielded median progression-free survival (PFS) of 6.2, 5.30, and 4.07 months (P = 0.041) and median OS of 21.2, 27.6, and 13.6 months (P = 0.193). In later-line therapy, taxane-based regimens achieved a median PFS of 6.93 months, outperforming camptothecin-based (1.13 months) and other regimens (1.90 months; P = 0.049). High evolutionary diversity was associated with shorter post-transformation OS (6.77 vs. 11.10 months), with restricted cubic spline analysis showing a nonsignificant trend toward a nonlinear association (P = 0.055).Age, RB1/NTRK1 mutation, and secondary T790M mutation were identified as independent risk factors and integrated into a predictive model with high accuracy. CONCLUSIONS: This study establishes a clinically applicable model for early prediction and risk stratification of SCLC transformation. Taxane-based regimens emerge as a promising later-line therapeutic option for T-SCLC.

Humans↗

PubMed2026

Circulating tumor cells identify a disseminated genomic high-risk phenotype within IMS-IMWG 2025 staging in newly diagnosed multiple myeloma.

The 2025 IMS-IMWG consensus genomic staging (CGS) system has improved genomic risk stratification in newly diagnosed multiple myeloma (NDMM), yet does not capture whether high-risk clones have acquired a disseminated phenotype. We investigated whether circulating tumor cells (CTC) refine CGS and enable longitudinal residual disease monitoring. We retrospectively analyzed 631 MM patients from the NICHE cohort (NCT04645199) who underwent CTC assessment across disease phases. Among 410 patients assessed at diagnosis, CTC were detectable in 63.9% and correlated with both bone marrow plasma cell infiltration and accumulation of high-risk cytogenetic abnormalities. In 359 NDMM patients with adequate follow-up, a cohort-derived CTC threshold of 0.38% independently predicted inferior progression-free survival (PFS) after multivariable adjustment. Importantly, CTC refined prognostic stratification specifically within the CGS high-risk subgroup. Patients with CGS high-risk/CTC-high disease had the shortest PFS, thereby defining a disseminated genomic high-risk phenotype comprising 12.4% (39/314) of evaluable NDMM patients. In follow-up cohorts, detectable CTC were associated with inferior outcomes in 127 patients assessed during non-progressive disease states, whereas combined CTC and bone marrow minimal residual disease assessment stratified outcomes in 120 patients with paired measurements. Overall, CTC-integrated CGS supports minimally invasive baseline risk stratification and longitudinal disease monitoring.

Journal Article↗

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↗

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↗

PubMed2025

Covering medical care costs for participants in the eMERGE Network: Challenges for equity and implementation.

PURPOSE: To investigate the complexities of covering study-recommended medical care costs for individuals (in order to prevent lack of adherence due to financial reasons), which have received little attention. METHODS: We explored the deliberations, decisions, and challenges faced by the Electronic Medical Records and Genomics (eMERGE) Network during the implementation of a genomic research project recommending clinical care based on high-risk results defined largely by polygenic risk scores. Two surveys were disseminated to eMERGE sites: to identify preferences about payment for specific care recommendations (survey 1) and to understand the operational processes of covering medical care costs (survey 2). RESULTS: Paying for a subset of care recommendations for the funded study duration was identified as the most feasible approach for covering medical care costs for participants who received high-risk genomic results. Each eMERGE site, by necessity, used diverse approaches to pay for medical care costs. CONCLUSION: eMERGE researchers balanced competing concerns about bias, equity, study design, regulatory compliance, and cost in designing a unified approach to cover some of the recommended medical care costs in the study. Many implementation challenges were encountered. Findings can inform researchers and regulatory bodies about the implications and complications of covering medical care costs in translational research studies focused on prevention.

Humans↗

PubMed2026

Understanding randomized controlled trial generalizability through an embedded molecular diagnostics trial.

BACKGROUND: Issues with randomized controlled trial generalizability are well described, but whether these issues result from differences in patient treatment across contexts remains unknown. We studied treatment of patients with high-risk prostate cancer after radical prostatectomy inside and outside a randomized controlled trial evaluating the impact of a genomic classifier on post-radical prostatectomy treatment decision making (Genomics in Michigan Impacting Observation of Radiation [G-MINOR]; ClinicalTrials.gov identifier NCT02783950). METHODS: G-MINOR enrolled 338 patients; propensity score-matched eligible but unenrolled patient cohorts (pretrial and trial contemporary) from the Michigan Urological Surgery Improvement Collaborative (MUSIC), in which the trial was embedded, were compared for rates and time to secondary treatment (adjuvant or salvage therapy) after prostatectomy. RESULTS: Among 338 patients in the G-MINOR cohort, 69 (31 adjuvant, 38 salvage) received secondary treatment compared with 266 (183 adjuvant, 83 salvage) and 104 (60 adjuvant, 44 salvage) in the 1014 contemporary and 338 pretrial-matched MUSIC cohorts. Time to secondary treatment was much shorter in the MUSIC cohort across all comparisons. For example, matching G-MINOR to synchronous MUSIC patients demonstrated 84% vs 74% estimated 2-year treatment-free survival for trial and real-world patients, respectively (P < .001). CONCLUSIONS: Controlling for key clinicopathologic factors, patients in the G-MINOR randomized controlled trial and MUSIC cohorts were treated differently, even after stratifying by genomic risk. These findings suggest that challenges in randomized controlled trial generalizability extend beyond the representativeness of trial participants. Differences in management may also explain why divergent patient outcomes are observed in randomized controlled trials vs real-world settings.

Aged↗

PubMed2026

Polygenic Risk Identifies Older Adults Who May Benefit From Aspirin for the Primary Prevention of Ischemic Stroke.

BACKGROUND: Low-dose aspirin is no longer recommended for routine primary prevention in older adults due to bleeding risks outweighing vascular benefits. We hypothesized that an integrative polygenic score (iPGS) could identify a subgroup of older individuals who derive net benefit from aspirin for the primary prevention of ischemic stroke. METHODS: We performed post hoc analysis of the ASPREE randomized, placebo-controlled trial (Aspirin in Reducing Events in the Elderly) of daily 100-mg aspirin, in 12 031 genotyped participants of European ancestry aged >70 years without prior cardiovascular disease. The iPGS was derived from >1.2 million variants and evaluated both continuously and by quintiles. Cox models assessed associations between polygenic risk, ischemic stroke, and major bleeding events, and tested the interaction between the iPGS and treatment allocation, with adjustment for baseline lifestyle and clinical covariates. RESULTS: The mean age of participants was 75.1 years, and 54.9% were women. Over a median of 4.6 years, 187 ischemic strokes and 373 major bleeds occurred, including 101 intracranial bleeds (46 hemorrhagic strokes). Each 1-SD increase in the iPGS was associated with higher incident ischemic stroke risk (hazard ratio, 1.39 [95% CI, 1.20-1.62]). An interaction between the continuous iPGS and aspirin allocation was observed for ischemic stroke (P=0.04) but not major bleeding. In the highest iPGS quintile, aspirin reduced ischemic stroke by 51% (hazard ratio, 0.49 [95% CI, 0.28-0.85]) without significantly increasing major bleeding (hazard ratio, 1.15 [95% CI, 0.71-1.88]). No benefit was observed in the overall cohort or in lower-risk quintiles. CONCLUSIONS: Among older adults, high polygenic risk identifies individuals who may experience substantial stroke reduction with aspirin, with no excess bleeding. These findings raise the possibility that genomic risk stratification may enable targeted aspirin use for the primary prevention of ischemic stroke. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01038583.

Humans↗

PubMed2025

Shared genetic risk and causal associations between Post-traumatic stress disorder and migraine with antithrombotic agents and other medications.

Post-traumatic stress disorder (PTSD) is a psychiatric disorder that frequently co-occurs with pain disorders including migraine. There are proposed biological, genetic and environmental factors associated with both PTSD and migraine suggesting shared etiology. Genome-Wide Association Studies (GWAS) have been used to identify genomic risk loci associated with various disorders and to investigate genetic overlap between traits. There is a significant genetic correlation between PTSD and migraine with no evidence of a causal relationship that could be attributed to pleiotropy. Cross-disorder genetic analyses were applied to investigate the genetic overlap and causal associations using GWAS summary statistics of PTSD (n = 214408), migraine (n = 873341) and 23 medication use traits (n = 78808-305913) including anti-depressants, anti-migraine preparations and beta-blocking agents. Across the entire genome, anti-thrombotic agents had a significant and negative genetic correlation with PTSD (rG = -0.2, P FDR = 0.032) and a positive genetic correlation with migraine (rG = 0.26, P FDR = 2.23 x 10-8). PTSD showed significant genetic correlation with 11 other medication use traits including beta blocking agents (rG = -0.11, P FDR = 0.034). Of the 2495 genomic regions tested, PTSD showed significant local genetic correlation with 12 medication use traits at 43 loci; while migraine showed significant genetic correlation with only anti-inflammatory agents and anti-rheumatic products at locus 12:57522282-57607142 (DAB1) (P < 2 x 10-5). The genetic liability to PTSD had a causal effect on increased risk of using pain medication such as opioids (β ivw = 0.59, P = 5.21 x 10-5) while the genetic liability to migraine had a causal effect on the increased risk of using anti-thrombotic agents (β ivw = 0.59, P = 1.69 x 10-7). The genes in the genomic regions shared between PTSD and medication use traits were enriched in neural-related pathways such as neuron development, neurogenesis and protein kinase activity. These results provide further insight into the genetically controlled biological and environmental factors underlying the shared etiology between PTSD and migraine. The identified biomarkers can be used as a basis for investigation as potential drug targets for both disorders. These findings are significant for drug re-purposing and treatment of PTSD and migraine using monotherapy.

GWAS↗

PubMed2026

Multi-ancestry multi-trait analysis reveals shared genetics across major psychiatric disorders and Alzheimer's disease.

The clinical overlap between major psychiatric disorders (MPDs) and Alzheimer's disease (AD) implicates complex shared etiology. Previous studies demonstrated that both diseases are genetically complex and highly heritable, suggesting that more endeavors are necessary to be made from the very bottom to understand their genetic basis. With the advance of post-genomic analysis, multi-ancestry meta-analysis allows the generalizability of the genetic architecture across different populations to uncover ancestry-specific variants, while multi-trait analysis enables the discovery of the co-colocalized risk genomic regions across diseases. Therefore, in this study, we leveraged published GWAS summary statistics from European, East Asian, Hispanic and African American populations to report schizophrenia, major depressive disorders, and Alzheimer's disease risk loci and further fine-mapping to credible sets with >95% PP inclusion of the causal variant. We distilled 2871 potential traits from publicly available and found 134 traits significantly genetically correlated with both MPDs and AD using batch LD score regression. We then prioritized the identified loci from multi-ancestry results for cross-trait colocalization analysis to assess shared genetic etiology and further nominated 2 colocalized loci across both conditions, including rs2532240 and rs6504163. In the end, we finalized our analysis by validation and functional inference of the underlying susceptibility genes as well as putative mechanisms using evidence from multiple resources, including FIVEx, Open Targets, and scQTLbase.

Humans↗