Abstract We performed a new melanoma GWAS meta-analysis, roughly doubling the sample size to ∼70,000 cases compared to the most recent study by Landi and colleagues. In the new meta-analysis, we identify 116 independent risk loci, replicating 52/54 loci previously reported. Post-GWAS variant-to-gene mapping remains critical to functionally interpret new loci discovered by this analysis. Most loci contain many candidate causal variants in linkage disequilibrium, with very few altering protein-coding sequence, suggesting cis-regulatory function underlying the majority of loci. Quantitative trait locus (QTL) colocalization methods can effectively prioritize target genes at susceptibility loci but many loci remain without assigned targets, perhaps reflecting context-specific variant effects not well-reflected in QTL datasets. To complement QTLs and more comprehensively identify potential causal genes, including those beyond 1 Mb, we applied H3K27ac-HiChIP in human primary melanocytes, the cell type of origin for melanoma. H3K27ac-HiChIP combines a Hi-C approach with a H3K27ac ChIP step to detect enhancer-promoter interactions at the risk loci. Statistically significant chromatin interactions were identified using the FitHiChIP pipeline. We subsequently performed variant-to-gene (V2G) mapping at all genome-wide significant melanoma loci, nominating target genes where fine-mapped variants overlapped or physically interacted with their respective promoters. HiChIP-based V2G mapping approach identified target genes at 94% loci (779 genes nominated at 109/116 loci), outperforming other gene nomination approaches (QTL colocalization, protein-coding variants), which nominated 102 candidate genes at 57% of risk loci (67/116 loci). Among genes identified by melanocyte or melanoma eQTL colocalization, a majority (19 of 32) were also nominated by V2G mapping. Likewise, 3 of 5 splice QTL genes and 21 of 34 meQTL genes overlapped with the V2G gene set. Next, we compared gene sets including the V2G mapping-identified candidates to those identified solely by QTLs and protein-coding variants. The gene set incorporating V2G candidates showed significant enrichment for oncogenic signaling pathways, including WNT/β-catenin signaling (FDR: Pwith V2G gene set= 6.3 × 10-05 vs Pwithout V2G gene set= 0.2), aryl hydrocarbon receptor signaling (P= 1.6 × 10-4 vs 0.2), and signaling by NOTCH1 (P=0.002 vs0.5). Notably, V2G mapping linked risk-associated variants to known cancer drivers (e.g. PIK3CA, NOTCH2, MDM4etc.) at 46% of loci (53/116; nominated 76 cancer drivers), with several located >1Mb away. Strikingly, we detected a highly significant long-range interaction (∼2 Mb) connecting fine-mapped variants near the locus 8q24.21 to cancer driver MYC. Overall, H3K27ac-HiChIP-based V2G mapping greatly improves the interpretation of melanoma susceptibility loci by identifying distant susceptibility genes, highlighting known cancer drivers as potential targets, and revealing that these loci converge on key oncogenic signaling pathways. Citation Format: Rohit Thakur, G J M Shanika R Jayasinghe, Mai Xu, Linh Bui-Raborn, Jianxin Shi, Diptavo Dutta, Phuc H. Hoang, Mathias Seviiri, Christopher I. Amos, Andrew Bakshi, Anne E. Cust, Florence Demenais, David L. Duffy, Lars G. Fritsche, Jiali Han, Nicholas K. Hayward, Kiarash Khosrotehrani, Rajiv Kumar, John F. Thompson, Stuart MacGregor, Miguel Renteria, Diane T. Smelser, Sarah V. Ward, Maria Concetta Fargnoli, Paola Ghiorzo, Alisa M. Goldstein, Chiara Menin, David Millan-Esteban, Eduardo Nagore, Cristina Pellegrini, Susana Puig, Alex Stratigos, David C. Whiteman, Melanoma Meta-Analysis Consortium, Lee E. Whelees, Rebecca I. Hartman, Maria Teresa Landi, Matthew H. Law, Kevin M. Brown. H3K27ac-HiChIP variant-to-gene mapping confirms the importance of cancer drivers and oncogenic signaling pathways in melanoma risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB384.

The extent to which genetic predisposition contributes to late-life depression risk, particularly after age 70, remains unclear, despite the high prevalence of depression in this age group and the variability in risk factors by age. This study investigated the association between a polygenic score (PGS) and depression outcomes, including severity, trajectories of depression, and antidepressant medication use, in a longitudinal cohort of 12,029 genotyped older adults of European descent aged ≥70 years, with no history of diagnosed cardiovascular disease events, dementia, or permanent physical disability at baseline. Participants were followed for a median of 4.7 years. The PGS was derived using the latest Psychiatric Genomics Consortium data for major depression. Depression was defined by the CES-D-10 score thresholds of ≥8 (primary outcome), ≥10, and ≥12 (secondary outcomes), alongside antidepressant medication use and four previously established longitudinal trajectories of depressive symptoms: low (non-depressed), moderate (subthreshold), high (persistent), and initially low but increasing (emerging). Multivariable models were used to examine associations between the PGS (per standard deviation, SD) and outcomes, adjusting for covariates. At baseline, mean participant age was 75.1 years, 54.9% were female, and 9.1% had depression (CES-D-10 ≥ 8). The PGS was significantly associated with baseline depression (OR = 1.23 [1.15–1.31]), incident depression (HR = 1.18 [1.14–1.23]) and antidepressant medication use (OR = 1.39 [1.31–1.47]). Compared with non-depressed participants, the PGS was associated with increasing severity of depression trajectory classes (subthreshold depression OR = 1.15 [1.11–1.20], emerging depression OR = 1.22 [1.13–1.31], persistent depression OR = 1.40 [1.31–1.49]). These findings suggest that the PGS may play an important role in risk stratification for late-life depression.

Neuroendocrine prostate cancer (NEPC) tumours are classified by pathology into several distinct subtypes. Gene expression profiling has revealed transcriptional heterogeneity across NEPC, but this is rarely considered in the context of variation between pathologies. Diagnosis typically relies on immunohistochemical markers (CHGA, SYP, NCAM1) and genomic alterations in RB1, PTEN and TP53. We hypothesized that NEPC pathologies have unique transcriptional features. Single‐cell RNA sequencing of 18 632 tumour cells from nine patient‐derived xenograft models representing five pathologies (small‐cell and large‐cell neuroendocrine carcinomas, focal neuroendocrine differentiation (Focal NED), low‐grade neuroendocrine and amphicrine) demonstrated pathway‐specific enrichment. Focal NED and amphicrine tumours exhibited cellular subpopulations enriched for KRAS, IL2‐STAT5 and TNF signalling pathways, absent in small‐ and large‐cell carcinomas, which were instead enriched for Myc and E2F pathways. Furthermore, focal NED cells exhibited minimal clonal divergence from adjacent adenocarcinoma cells, while small cell carcinoma cells were clonally distinct. These data underscore significant transcriptional variation among NEPC pathologies, highlighting focal NED's unique biological context and its clinical implications.

Summary: Background: Oestrone, predominantly made in fat, is the main circulating oestrogen and important for target tissue oestradiol production in women after menopause. The present study was undertaken to determine the genetic regulation of blood oestrone, measured with precision, in postmenopausal women and to explore associations between the identified genetic loci and endometrial cancer in a large, independent cohort. Methods: A genome-wide association study (GWAS) was undertaken in women aged at least 70 years to identify genetic associations with blood oestrone concentrations measured by liquid chromatography and tandem mass spectrometry. The GWAS included participants from the Sex Hormones in Older Women (SHOW) study, a sub-study of the longitudinal ASPREE (ASPirin in Reducing Events in the Elderly) randomised trial. Of the 6358 women providing a biobank sample at enrolment, 4951 unrelated women of European ancestry, not taking sex hormones, anti-oestrogens, anti-androgens or systemic glucocorticoids were included in the GWAS. Single nucleotide polymorphisms (SNPs) from loci identified below the genome-wide significance threshold were then tested in an independent cohort (the UK Biobank) for association with endometrial cancer risk, using logistic regression and adjusting for age, body mass index (BMI) and the top 10 genetic principal components. Findings: The median age of the 4951 women included in the GWAS was 75.9 years (range 70–94.8 years). The GWAS identified four independent SNPs associated with oestrone concentrations (p < 5 × 10−8). Among them, the effect (minor) alleles rs34670419-T, rs2846729-T and rs2414098-T were associated with lower oestrone concentrations. Carrying these effect alleles was associated with lower oestrone concentrations in a dose-dependent manner. The effect allele rs56400819-A was associated with higher oestrone concentrations. When applied to UK Biobank, carrier status for rs2414098-T associated with the CYP19A1 gene which encodes the aromatase enzyme required for oestrogen synthesis was significantly associated with lower endometrial cancer risk (adjusted odd ratio [aOR] 0.87 [95% CI 0.82–0.93]; p = 6.69 × 10−5 for women across all ages and aOR 0.89 [95% CI 0.83–0.96]; p = 0.003 for postmenopausal women). None of the models that included age, body mass index (BMI), the top 10 genetic principal components, parity and diabetes mellitus explained more than 7.6% of the variation in risk. Interpretation: We have shown genetic regulation of oestrone concentrations in postmenopausal women, and that SNPs associated with oestrone were also associated with endometrial cancer risk, independent of BMI, parity and diabetes mellitus. Although the apparent contribution was modest, the biological influence of oestrone concentrations may be greater through conversion to oestradiol in endometrial tissue. Funding: The ASPREE trial was supported by the National Institute on Aging and the National Cancer Institute at the National Institutes of Health (Grant U01AG029824); the National Health and Medical Research Council (NHMRC) of Australia (Grant 34047, 1127060); Monash University (Australia); and the Victorian Cancer Agency (Australia). The ASPREE Healthy Ageing Biobank was funded by the CSIRO (Flagship Grant), the National Cancer Institute (Grant U01 AG029824) and Monash University. This analysis of sex hormones was funded by an NHMRC of Australia Project Grant (No. 1105305). SRD holds an NHMRC Investigator Grant (2016627). PL is supported by a National Heart Foundation Future Leader Fellowship (102604).

Background Men with neuroendocrine prostate cancer (NEPC) have a poor prognosis. NEPC is commonly diagnosed by immunohistochemical markers (CHGA, SYP and NCAM1) and genomic features (mutations in RB1, PTEN, TP53). But by pathology, NEPC tumours are variable, leading to a classification of NE subtypes such as small cell and large cell neuroendocrine carcinomas, focal neuroendocrine differentiation (Focal NED), and Amphicrine. We postulated the diversity observed in NEPC pathologies might arise from differences in transcriptional profiles and the aim of this study is to utilize single-cell RNA sequencing to define the transcriptional differences between NEPC subtype pathologies. Methods Gene expression profiles were obtained for 18,632 individual tumour cells from 9 patient-derived xenograft (PDX) models representing five distinct neuroendocrine pathologies of prostate cancer. Integration and clustering of cell-level data demarked transcriptionally distinct sub-populations of cells. Differential gene expression, gene set enrichment and transcriptional factor regulon analysis identified expression signatures unique to specific neuroendocrine pathologies. Copy-number estimated from expression data revealed the clonal structure of PDXs with mixed adenocarcinoma and neuroendocrine pathologies. Results Significant differences were observed in the transcriptional profiles of NEPC pathology subtypes. Focal NED cells maintain AR signaling, similar to the amphicrine subtype but different from small and large cell carcinomas. Cellular sub-populations enriched for expression of KRAS, IL2-STAT5 and TNF-signaling genes were found in focal NED and amphicrine pathologies, but not in small or large cell carcinomas. In contrast, sub-populations enriched for the YAP, Myc and E2F pathways were detected in small cell, large cell and amphicrine tumours, but not in focal NED cells. Each pathology showed unique patterns of master regulator activity as well, further implicating focal NED as a transcriptionally distinct entity. Based on copy number alterations within PDXs of mixed pathology, focal NED cells showed little clonal divergence from neighboring adenocarcinoma cells, whereas cells with small cell neuroendocrine pathology were clonally distinct. Conclusions Neuroendocrine prostate cancer subtypes can be identified by pathology and our study shows that transcriptional features identified by single-cell RNA-sequencing also distinguish neuroendocrine subtypes pathologies from each other. In particular, our data redefine focal neuroendocrine differentiation as a pathology expressing androgen receptors (AR), exhibiting its distinctive composition of transcriptionally unique sub-populations. These findings advocate for differences in the treatment of NEPC tumors, particularly those displaying focal NED. ### Competing Interest Statement The authors have declared no competing interest.

Fears of genetic discrimination in life insurance continue to deter some Australians from genetic testing. In July 2019, the life insurance industry introduced a partial, self-regulated moratorium restricting the use of genetic results in underwriting, applicable to policies up to certain limits (eg AUD$500,000 for death cover). We administered an online survey to consumers who had taken, or been offered, clinical genetic testing for adult-onset conditions, to gather views and experiences about the moratorium and the use of genetic results in life insurance, including its regulation. Most respondents (n = 367) had undertaken a genetic test (89%), and had a positive test result (76%; n = 243/321). Almost 30% (n = 94/326) reported testing after 1 July 2019. Relatively few respondents reported knowing about the moratorium (16%; n = 54/340) or that use of genetic results in life insurance underwriting is legal (17%; n = 60/348). Only 4% (n = 14/350) consider this practice should be allowed. Some respondents reported ongoing difficulties accessing life insurance products, even after the moratorium. Further, discrimination concerns continue to affect some consumers’ decision-making about having clinical testing and applying for life insurance products, despite the Moratorium being in place. Most respondents (88%; n = 298/340) support the introduction of legislation by the Australian government to regulate this issue. Despite the introduction of a partial moratorium in Australia, fears of genetic discrimination persist, and continue to deter people from genetic testing. Consumers overwhelmingly consider life insurers should not be allowed to use genetic results in underwriting, and that federal legislation is required to regulate this area.

Gene-based association tests aggregate multiple SNP-trait associations into sets defined by gene boundaries and are widely used in post-GWAS analysis. A common approach for gene-based tests is to combine SNPs associations by computing the sum of χ2 statistics. However, this strategy ignores the directions of SNP effects, which could result in a loss of power for SNPs with masking effects, e.g., when the product of two SNP effects and the linkage disequilibrium (LD) correlation is negative. Here, we introduce “mBAT-combo,” a set-based test that is better powered than other methods to detect multi-SNP associations in the context of masking effects. We validate the method through simulations and applications to real data. We find that of 35 blood and urine biomarker traits in the UK Biobank, 34 traits show evidence for masking effects in a total of 4,273 gene-trait pairs, indicating that masking effects is common in complex traits. We further validate the improved power of our method in height, body mass index, and schizophrenia with different GWAS sample sizes and show that on average 95.7% of the genes detected only by mBAT-combo with smaller sample sizes can be identified by the single-SNP approach with a 1.7-fold increase in sample sizes. Eleven genes significant only in mBAT-combo for schizophrenia are confirmed by functionally informed fine-mapping or Mendelian randomization integrating gene expression data. The framework of mBAT-combo can be applied to any set of SNPs to refine trait-association signals hidden in genomic regions with complex LD structures.

Background The risk of atherosclerotic cardiovascular disease (ASCVD) increases sharply with age. Some older individuals, however, remain unaffected despite high predicted risk. These individuals may carry cardioprotective genetic variants that contribute to resilience. Our aim was to assess whether asymptomatic older individuals without prevalent ASCVD carry cardioprotective genetic variants that contribute to ASCVD resilience. Methods and Results We performed a genome‐wide association study using a 10‐year predicted ASCVD risk score as a quantitative trait, calculated only in asymptomatic older individuals aged ≥70 years without prevalent ASCVD. Our discovery genome‐wide association study of N=12 031 ASCVD event‐free individuals from the ASPREE (Aspirin in Reducing Events in the Elderly) trial identified 2 independent variants, rs9939224 ( P <5×10 −8 ) and rs56156922 ( P <10 −6 ), in the CETP (cholesteryl ester transfer protein) gene. The CETP gene is a regulator of plasma high‐density lipoprotein cholesterol, low‐density lipoprotein cholesterol, and lipoprotein(a) levels, and it is a therapeutic drug target. The associations were replicated in the UK Biobank (subpopulation of N=13 888 individuals aged ≥69 years without prevalent ASCVD). Carriers of the identified CETP variants (versus noncarriers) had higher plasma high‐density lipoprotein cholesterol levels, lower plasma low‐density lipoprotein cholesterol levels, and reduced risk of incident ASCVD events during follow‐up. Expression quantitative trait loci analysis predicted the identified CETP variants reduce CETP gene expression across various tissues. Previously reported associations between genetic CETP inhibition and increased risk of age‐related macular degeneration were not observed among the 3917 ASPREE trial participants with retinal imaging and genetic data available. Conclusions Common genetic variants in the CETP gene region are associated with cardiovascular resilience during aging. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01038583.

Supplementary Methods, Figures, and Tables

Kidney function is strongly influenced by genetic factors with both monogenic and polygenic factors contributing to kidney function. Monogenic disorders with primarily autosomal dominant inheritance patterns account for 10% of adult and 50% of paediatric kidney diseases. However, kidney function is also a complex trait with polygenic architecture, where genetic factors interact with environment and lifestyle factors. Family studies suggest that kidney function has significant heritability at 35–69%, capturing complexities of the genome with shared environmental factors. Genome-wide association studies estimate the single nucleotide polymorphism-based heritability of kidney function between 7.1 and 20.3%. These heritability estimates, measuring the extent to which genetic variation contributes to CKD risk, indicate a strong genetic contribution. Polygenic Risk Scores have recently been developed for chronic kidney disease and kidney function, and validated in large populations. Polygenic Risk Scores show correlation with kidney function but lack the specificity to predict individual-level changes in kidney function. Certain kidney diseases, such as membranous nephropathy and IgA nephropathy that have significant genetic components, may benefit most from polygenic risk scores for improved risk stratification. Genetic studies of kidney function also provide a potential avenue for the development of more targeted therapies and interventions. Understanding the development and validation of genomic scores is required to guide their implementation and identify the most appropriate potential implications in clinical practice. In this review, we provide an overview of the heritability of kidney function traits in population studies, explore both monogenic and polygenic concepts in kidney disease, with a focus on recently developed polygenic risk scores in kidney function and chronic kidney disease, and review specific diseases which are most amenable to incorporation of genomic scores. Graphical abstract

Risk of chronic kidney disease (CKD) is influenced by environmental and genetic factors and increases sharply in individuals 70 years and older. Polygenic scores (PGS) for kidney disease-related traits have shown promise but require validation in well-characterized cohorts. Here, we assessed the performance of recently developed PGSs for CKD-related traits in a longitudinal cohort of healthy older individuals enrolled in the Australian ASPREE randomized controlled trial of daily low-dose aspirin with CKD risk at baseline and longitudinally. Among 11,813 genotyped participants aged 70 years or more with baseline eGFR measures, we tested associations between PGSs and measured eGFR at baseline, clinical phenotype of CKD, and longitudinal rate of eGFR decline spanning up to six years of follow-up per participant. A PGS for eGFR was associated with baseline eGFR, with a significant decrease of 3.9 mL/min/1.73m2 (95% confidence interval -4.17 to -3.68) per standard deviation (SD) increase of the PGS. This PGS, as well as a PGS for CKD stage 3 were both associated with higher risk of baseline CKD stage 3 in cross-sectional analysis (Odds Ratio 1.75 per SD, 95% confidence interval 1.66-1.85, and Odds Ratio 1.51 per SD, 95% confidence interval 1.43-1.59, respectively). Longitudinally, two separate PGSs for eGFR slope were associated with significant kidney function decline during follow-up. Thus, our study demonstrates that kidney function has a considerable genetic component in older adults, and that new PGSs for kidney disease-related phenotypes may have potential utility for CKD risk prediction in advanced age.

BackgroundPopulation-based DNA screening for medically actionable conditions has the potential to improve public health by enabling early detection, treatment and/or prevention; however, public attitudes and willingness to participate in DNA screening have not been well investigated. MethodsWe presented a scenario to members of the Australian public, randomly selected from the electoral roll via the Australian Survey of Societal Attitudes, describing an adult population DNA screening programme currently under development, to detect risk of medically actionable cancers and heart disease. We asked questions regarding willingness to participate and pay, preferred delivery methods and concerns. ResultsWe received 1060 completed questionnaires (response rate 23%, mean age 58 years). The vast majority (>92%) expressed willingness to undertake DNA screening. When asked about the optimal age of screening, most (56%) favoured early adulthood (aged 18-40 years) rather than at birth or childhood. Many respondents would prefer samples and data be kept for re-screening (36%) or research use (43%); some preferred samples to be destroyed (21%). Issues that decrease likelihood of participation included privacy (75%) and insurance (86%) implications. ConclusionOur study demonstrates public willingness to participate in population DNA screening in Australia, and identifies barriers to participation, to be addressed in the design of screening programmes. Results are informing the development of a pilot national DNA screening programme.

ObjectivePrevention of osteoarthritis (OA) remains important, as there are no disease‐modifying treatments. A personalized approach has the potential to better target prevention strategies. In the present study, we used recently identified genetic risk variants from genome‐wide association analysis for advanced OA to calculate polygenic risk scores (PRS) for knee and hip OA and assessed PRS performance in an independent population of older community‐dwelling adults.MethodsPRS were calculated in 12,093 individuals of European genetic descent ages ≥70 years who were enrolled in the Aspirin in Reducing Events in the Elderly trial. The outcome measure was knee and hip replacement (hospitalizations during the trial and self‐reported joint replacements before enrollment). PRS were considered as continuous (per SD) and categorical (low risk [0–20%], medium risk [21–80%], high risk [81–100%]) variables. Logistic regression was used to examine associations between PRS and risk of joint replacement, adjusted for age, sex, body mass index, and socioeconomic status.ResultsAmong the participants, 1,422 (11.8%) had knee replacements and 1,297 (10.7%) had hip replacements. PRS (per SD) were associated with a risk of knee replacement (odds ratio [OR] 1.13 [95% confidence interval (95% CI) 1.07–1.20]) and hip replacement (OR 1.23 [95% CI 1.16–1.30]). Participants with high PRS had an increased risk of knee replacement (OR 1.44 [95% CI 1.20–1.73]) and hip replacement (OR 1.88 [95% CI 1.56–2.26]), compared to those with low PRS. Associations were stronger for PRS and hip replacement risk in women than in men. Associations were similar in sensitivity analyses that examined joint replacements before and during the trial separately.ConclusionPRS have the potential to improve prevention of severe knee and hip OA by providing a personalized approach and identifying individuals who may benefit from early intervention.

Abstract Although aspirin has been considered a promising agent for prevention of colorectal cancer, recent data suggest a lack of benefit among older individuals. Whether some individuals with higher risk of colorectal cancer may benefit from aspirin remains unknown. We used a 95-variant colorectal cancer polygenic risk score (PRS) to explore the association between genetic susceptibility to colorectal cancer and aspirin use in a prospective study of 12,609 individuals of European descent ages ≥70 years, enrolled in the ASPirin in Reducing Events in the Elderly (ASPREE) double-blinded, placebo-controlled randomized trial (randomized controlled trial; RCT). Cox proportional hazards models were used to assess the association of aspirin use on colorectal cancer, as well as the interaction between the PRS and aspirin treatment on colorectal cancer. Over a median of 4.7 years follow-up, 143 participants were diagnosed with incident colorectal cancer. Aspirin assignment was not associated with incidence of colorectal cancer overall [HR = 0.94; 95% confidence interval (CI), 0.68–1.30] or within strata of PRS (P for interaction = 0.97). However, the PRS was associated with an increased risk of colorectal cancer (HR = 1.28 per SD; 95% CI, 1.09–1.51). Individuals in the top quintile of the PRS distribution had an 85% higher risk compared with individuals in the bottom quintile (HR = 1.85; 95% CI, 1.08–3.15). In a prospective RCT of older individuals, a PRS is associated with incident colorectal cancer risk, but aspirin use was not associated with a reduction of incident colorectal cancer, regardless of baseline genetic risk. Prevention Relevance: There is strong evidence to support prophylactic aspirin use for the prevention of colorectal cancer. However recent recommendations suggest the risk of bleeding in older individuals outweighs the benefit. We sought to determine whether some older individuals might still benefit from aspirin based on their genetic susceptibility.

Background: The use of a polygenic risk score (PRS) to improve risk prediction of coronary heart disease (CHD) events has been demonstrated to have clinical utility in the general adult population. However, the prognostic value of a PRS for CHD has not been examined specifically in older populations of individuals aged ≥70 years, who comprise a distinct high-risk subgroup. The objective of this study was to evaluate the predictive value of a PRS for incident CHD events in a prospective cohort of older individuals without a history of cardiovascular events. Methods: We used data from 12 792 genotyped, healthy older individuals enrolled into the ASPREE trial (Aspirin in Reducing Events in the Elderly), a randomized double-blind placebo-controlled clinical trial investigating the effect of daily 100 mg aspirin on disability-free survival. Participants had no previous history of diagnosed atherothrombotic cardiovascular events, dementia, or persistent physical disability at enrollment. We calculated a PRS (meta-genomic risk score) consisting of 1.7 million genetic variants. The primary outcome was a composite of incident myocardial infarction or CHD death over 5 years. Results: At baseline, the median population age was 73.9 years, and 54.9% were female. In total, 254 incident CHD events occurred. When the PRS was added to conventional risk factors, it was independently associated with CHD (hazard ratio, 1.24 [95% CI, 1.08–1.42], P =0.002). The area under the curve of the conventional model was 70.53 (95% CI, 67.00–74.06), and after inclusion of the PRS increased to 71.78 (95% CI, 68.32–75.24, P =0.019), demonstrating improved prediction. Reclassification was also improved, as the continuous net reclassification index after adding PRS to the conventional model was 0.25 (95% CI, 0.15–0.28). Conclusion: A PRS for CHD performs well in older people and improves prediction over conventional cardiovascular risk factors. Our study provides evidence that genomic risk prediction for CHD has clinical utility in individuals aged 70 years and older. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01038583

The pathophysiological basis for AF association with polygenic risk scores (PRS) is unknown.

BACKGROUND The role of aspirin in reducing lipoprotein(a)-mediated atherothrombotic events in primary prevention is not established. OBJECTIVES This study sought to assess whether low-dose aspirin benefits individuals with elevated plasma lipoprotein(a)-associated genotypes in the setting of primary prevention. METHODS The study analyzed 12,815 genotyped individuals $70 years of age of European ancestry and without prior cardiovascular disease events enrolled in the ASPREE (ASPirin in Reducing Events in the Elderly) ran-domized controlled trial of 100 mg/d aspirin. We defined lipoprotein(a)-associated genotypes using rs3798220-C carrier status and quintiles of a lipoprotein(a) genomic risk score (LPA-GRS). We tested for interaction between genotypes and aspirin allocation in Cox proportional hazards models for incidence of major adverse cardiovascular events (MACE) and clinically significant bleeding. We also examined associations in the aspirin and placebo arms of the trial separately. RESULTS During a median 4.7 years (IQR: 3.6-5.7 years) of follow-up, 435 MACE occurred, with an interaction observed between rs3798220-C and aspirin allocation (P 1/4 0.049). rs3798220-C carrier status was associated with increased MACE risk in the placebo group (HR: 1.90; 95% CI: 1.11-3.24) but not in the aspirin group (HR: 0.54; 95% CI: 0.17-1.70). High LPA-GRS (vs low) was associated with increased MACE risk in the placebo group (HR: 1.70; 95% CI: 1.14-2.55), with risk attenuated in the aspirin group (HR: 1.41; 95% CI: 0.90-2.23), but the interaction was not statistically significant. In all participants, aspirin reduced MACE by 1.7 events per 1,000 person-years and increased clinically significant bleeding by 1.7 events per 1,000 person-years. However, in the rs3798220-C and high LPA-GRS subgroups, aspirin reduced MACE by 11.4 and 3.3 events per 1,000 person-years respectively, without significantly increased bleeding risk. CONCLUSIONS Aspirin may benefit older individuals with elevated lipoprotein(a) genotypes in primary pre-vention. (J Am Coll Cardiol 2022;80:1287-1298) (c) 2022 by the American College of Cardiology Foundation.

Background: The use of a polygenic risk score (PRS) to predict coronary heart disease (CHD) events has been demonstrated in the general adult population. However, whether predictive performance extends to older individuals is unclear. Aim: To evaluate the predictive value of a PRS for incident CHD events in a prospective cohort of individuals aged 70 years and older. Methods: We used data from 12,792 genotyped participants of the ASPREE trial, a randomized placebo-controlled trial investigating the effect of daily 100mg aspirin on disability-free survival in healthy older people. Participants had no previous history of diagnosed atherothrombotic cardiovascular events, dementia, or persistent physical disability at enrolment. We calculated a PRS comprising 1.7 million genetic variants (metaGRS). The primary outcome was a composite of incident myocardial infarction or CHD death over 5 years. Results: At baseline, the median population age was 73.9 years and 54.9% were female. In total, 254 incident CHD events occurred. When the PRS was added to conventional risk factors, it was independently associated with CHD (hazard ratio 1.24 [95% confidence interval [CI] 1.08-1.42], p=0.002). The AUC of the conventional model was 70.53 (95%CI 67.00-74.06), and after inclusion of the PRS increased to 71.78 (95%CI 68.32-75.24, p=0.019), demonstrating improved prediction. Reclassification was also improved, as the continuous net reclassification index after adding PRS to the conventional model was 0.25 (95%CI 0.15-0.28). Conclusions: A PRS for CHD performs well in older people, suggesting that the clinical utility of genomic risk prediction for CHD extends to this distinct high-risk subgroup.