Biomedical subjects

Eimear E Kenny

Publications and source records attributed to Eimear E Kenny.

7 recordsLinked to original sources

PubMed2026

Additive value of polygenic risk and family history for coronary heart disease risk stratification in two diverse US cohorts.

Whether polygenic risk, monogenic familial hypercholesterolemia (FH), and family history (FamHx) are additively informative for coronary heart disease (CHD) risk prediction across self-identified race/ethnicity (SIRE) groups has not been established. In two diverse cohorts-Electronic Medical Records and Genomics (eMERGE) phase IV (eIV; n = 19,348) and All of Us (AoU; n = 239,645)-we quantified the associations of a polygenic risk score (PRSCHD), pathogenic/likely pathogenic variants in genes associated with FH, and FamHx with CHD and evaluated their incremental value when added to the pooled cohort equations (PCEs). CHD was defined as myocardial infarction, unstable angina, or coronary revascularization. We modeled associations with multivariable logistic regression (prevalent CHD in eIV) and Cox proportional hazards (incident CHD in AoU) and characterized predictive performance with the c-statistic and reclassification and decision-curve net benefits across actionable 10-year risk thresholds. The effects of PRSCHD and FamHx were independent and additive in both cohorts and consistent across White, Black, and Latino SIRE groups. In eIV, adding PRSCHD and FamHx to the PCE increased the c-statistic for prevalent CHD from 0.719 to 0.753 (p-diff = 9.1 × 10-3) and reclassified 18.8% of participants at the 7.5% 10-year threshold, yielding approximately 4 additional true-positive CHD identifications per 1,000 screened. Net benefit gains were observed between the 7.5% and 10% thresholds across all three SIRE groups. In conclusion, PRSCHD and FamHx were independently and additively associated with CHD across major SIRE groups in two diverse cohorts in the United States (US), motivating the addition of these factors to clinical risk algorithms.

Humans↗

PubMed2025

SPC: a SPectral Component approach leveraging Identity-by-Descent graphs to address recent population structure in genomic analysis.

Population structure is a well-known confounder in statistical genetics, particularly in genome-wide association studies (GWAS), where it can lead to inflated test statistics and spurious associations. Traditional methods, such as principal components (PCs), commonly used to adjust for population structure, are limited in capturing fine-scale, non-linear patterns that arise from recent demographic events - patterns that are crucial for understanding rare variant effects. To address this challenge, we propose a novel method called SPectral Components (SPCs), which leverages identity-by-descent (IBD) graphs to capture and transform local, non-linear fine-scale population structure into continuous representations that can be seamlessly integrated into genetic analysis pipelines. Using both simulated datasets and empirical data from the UK Biobank (N ≈ 420,000), we demonstrate that SPCs outperform PCs in adjusting for fine-scale population structure. In simulations, SPCs explained over 90% of the fine-scale population structure with fewer components, while PCs captured less than 5%. In the UK Biobank, SPCs reduced the inflation of p-values in the GWAS of an environmental-driven phenotype by 12% compared to PCs, while maintaining a similar performance to PCs in height, a highly heritable phenotype. Additionally, SPCs improved rare variant association analyses, reducing genomic inflation (e.g., from 7.6 to 1.2 in one analysis), and provided more accurate heritability estimates. Spatial autocorrelation analysis further confirmed the ability of SPCs to account for environmental effects, reducing Moran's I for both environmental and heritable phenotypes more effectively than PCs. Overall, our findings demonstrate that SPCs provide a robust, scalable adjustment for recent population structure, offering a powerful alternative or complement to PCs in large-scale biobank studies.

GWAS↗

PubMed2025

Rare damaging CCR2 variants are associated with lower lifetime cardiovascular risk.

BACKGROUND: Previous work has shown a role of CCL2, a key chemokine governing monocyte trafficking, in atherosclerosis. However, it remains unknown whether targeting CCR2, the cognate receptor of CCL2, provides protection against human atherosclerotic cardiovascular disease. METHODS: Computationally predicted damaging or loss-of-function (REVEL > 0.5) variants within CCR2 were detected in whole-exome-sequencing data from 454,775 UK Biobank participants and tested for association with cardiovascular endpoints in gene-burden tests. Given the key role of CCR2 in monocyte mobilization, variants associated with lower monocyte count were prioritized for experimental validation. The response to CCL2 of human cells transfected with these variants was tested in migration and cAMP assays. Validated damaging variants were tested for association with cardiovascular endpoints, atherosclerosis burden, and vascular risk factors. Significant associations were replicated in six independent datasets (n = 1,062,595). RESULTS: Carriers of 45 predicted damaging or loss-of-function CCR2 variants (n = 787 individuals) were at lower risk of myocardial infarction and coronary artery disease. One of these variants (M249K, n = 585, 0.15% of European ancestry individuals) was associated with lower monocyte count and with both decreased downstream signaling and chemoattraction in response to CCL2. While M249K showed no association with conventional vascular risk factors, it was consistently associated with a lower risk of myocardial infarction (odds ratio [OR]: 0.66, 95% confidence interval [CI]: 0.54-0.81, p = 6.1 × 10-5) and coronary artery disease (OR: 0.74, 95%CI: 0.63-0.87, p = 2.9 × 10-4) in the UK Biobank and in six replication cohorts. In a phenome-wide association study, there was no evidence of a higher risk of infections among M249K carriers. CONCLUSIONS: Carriers of an experimentally confirmed damaging CCR2 variant are at a lower lifetime risk of myocardial infarction and coronary artery disease without carrying a higher risk of infections. Our findings provide genetic support for the translational potential of CCR2-targeting as an atheroprotective approach.

Humans↗

PubMed2024

Evolving knowledge of red flag clinical features associated with TTR p.(Val142Ile) in a diverse electronic health-record-linked biobank.

PURPOSE: Previous studies have established red flags that raise clinical suspicion for the hereditary form of transthyretin amyloidosis (ATTRv). However, these have not been specifically evaluated for the most common associated variant, TTR p.(Val142Ile). METHODS: Using an ancestrally diverse electronic health-record-linked biobank with exome sequence data from 27,630 unrelated adults, we evaluated 9 ATTRv-related clinical features among TTR p.(Val142Ile)-positive and -negative individuals. RESULTS: Among 337 variant-positive individuals (median age 63, 60% female), 10 (3.0%) were diagnosed with amyloidosis. TTR p.(Val142Ile) was associated with increased odds of cardiomyopathy/heart failure (CM/HF), atrial fibrillation, polyneuropathy, carpal tunnel syndrome, and proteinuria, but only in individuals ≥60 years. These features were evident 1.7 to 7.7 years earlier in variant-positive vs -negative individuals (hazard ratio [HR] 1.37, P = 3.99 × 10-2; HR 1.78, P = 2.52 × 10-3; HR 1.78, P = 1.70 × 10-3; HR 1.81, P = 5.14 × 10-3; HR 1.60, P = 1.94 × 10-2, respectively). By age 50, the cumulative incidence of CM/HF was 3.5-fold higher, and by age 60, the incidences of CM/HF, polyneuropathy, and proteinuria were 2-fold higher in variant-positive individuals. CONCLUSION: This study clarifies red flags that are associated with TTR p.(Val142Ile) in an age-dependent manner. With modifying therapies being available, early diagnosis of ATTRv in variant-positive individuals through the recognition of key clinical features is paramount.

Humans↗

PubMed2024

Genetics of Latin American Diversity Project: Insights into population genetics and association studies in admixed groups in the Americas.

Latin Americans are underrepresented in genetic studies, increasing disparities in personalized genomic medicine. Despite available genetic data from thousands of Latin Americans, accessing and navigating the bureaucratic hurdles for consent or access remains challenging. To address this, we introduce the Genetics of Latin American Diversity (GLAD) Project, compiling genome-wide information from 53,738 Latin Americans across 39 studies representing 46 geographical regions. Through GLAD, we identified heterogeneous ancestry composition and recent gene flow across the Americas. Additionally, we developed GLAD-match, a simulated annealing-based algorithm, to match the genetic background of external samples to our database, sharing summary statistics (i.e., allele and haplotype frequencies) without transferring individual-level genotypes. Finally, we demonstrate the potential of GLAD as a critical resource for evaluating statistical genetic software in the presence of admixture. By providing this resource, we promote genomic research in Latin Americans and contribute to the promises of personalized medicine to more people.

Humans↗

PubMed2024

Rare variant contribution to the heritability of coronary artery disease.

Whole genome sequences (WGS) enable discovery of rare variants which may contribute to missing heritability of coronary artery disease (CAD). To measure their contribution, we apply the GREML-LDMS-I approach to WGS of 4949 cases and 17,494 controls of European ancestry from the NHLBI TOPMed program. We estimate CAD heritability at 34.3% assuming a prevalence of 8.2%. Ultra-rare (minor allele frequency ≤ 0.1%) variants with low linkage disequilibrium (LD) score contribute ~50% of the heritability. We also investigate CAD heritability enrichment using a diverse set of functional annotations: i) constraint; ii) predicted protein-altering impact; iii) cis-regulatory elements from a cell-specific chromatin atlas of the human coronary; and iv) annotation principal components representing a wide range of functional processes. We observe marked enrichment of CAD heritability for most functional annotations. These results reveal the predominant role of ultra-rare variants in low LD on the heritability of CAD. Moreover, they highlight several functional processes including cell type-specific regulatory mechanisms as key drivers of CAD genetic risk.

Humans↗

PubMed2024

The Genetic Determinants and Genomic Consequences of Non-Leukemogenic Somatic Point Mutations.

Clonal hematopoiesis (CH) is defined by the expansion of a lineage of genetically identical cells in blood. Genetic lesions that confer a fitness advantage, such as point mutations or mosaic chromosomal alterations (mCAs) in genes associated with hematologic malignancy, are frequent mediators of CH. However, recent analyses of both single cell-derived colonies of hematopoietic cells and population sequencing cohorts have revealed CH frequently occurs in the absence of known driver genetic lesions. To characterize CH without known driver genetic lesions, we used 51,399 deeply sequenced whole genomes from the NHLBI TOPMed sequencing initiative to perform simultaneous germline and somatic mutation analyses among individuals without leukemogenic point mutations (LPM), which we term CH-LPMneg. We quantified CH by estimating the total mutation burden. Because estimating somatic mutation burden without a paired-tissue sample is challenging, we developed a novel statistical method, the Genomic and Epigenomic informed Mutation (GEM) rate, that uses external genomic and epigenomic data sources to distinguish artifactual signals from true somatic mutations. We performed a genome-wide association study of GEM to discover the germline determinants of CH-LPMneg. After fine-mapping and variant-to-gene analyses, we identified seven genes associated with CH-LPMneg (TCL1A, TERT, SMC4, NRIP1, PRDM16, MSRA, SCARB1), and one locus associated with a sex-associated mutation pathway (SRGAP2C). We performed a secondary analysis excluding individuals with mCAs, finding that the genetic architecture was largely unaffected by their inclusion. Functional analyses of SMC4 and NRIP1 implicated altered HSC self-renewal and proliferation as the primary mediator of mutation burden in blood. We then performed comprehensive multi-tissue transcriptomic analyses, finding that the expression levels of 404 genes are associated with GEM. Finally, we performed phenotypic association meta-analyses across four cohorts, finding that GEM is associated with increased white blood cell count and increased risk for incident peripheral artery disease, but is not significantly associated with incident stroke or coronary disease events. Overall, we develop GEM for quantifying mutation burden from WGS without a paired-tissue sample and use GEM to discover the genetic, genomic, and phenotypic correlates of CH-LPMneg.

Journal Article↗