Atrial Fibrillation and Clonal Hematopoiesis in TET2 and ASXL1.

Importance: Clonal hematopoiesis of indeterminate potential (CHIP) may contribute to the risk of atrial fibrillation (AF) through its association with inflammation and cardiac remodeling. Objective: To determine whether CHIP was associated with AF, inflammatory and cardiac biomarkers, and cardiac structural changes. Design, Setting, and Participants: This was a population-based, prospective cohort study in participants of the Atherosclerosis Risk in Communities (ARIC) study and UK Biobank (UKB) cohort. Samples were collected and echocardiography was performed from 2011 to 2013 in the ARIC cohort, and samples were collected from 2006 to 2010 in the UKB cohort. Included in this study were adults without hematologic malignancies, mitral valve stenosis, or previous mitral valve procedure from both the ARIC and UKB cohorts; additionally, participants without hypertrophic cardiomyopathy and congenital heart disease from the UKB cohort were also included. Data analysis was completed in 2023. Exposures: CHIP (variant allele frequency [VAF] ≥2%), common gene-specific CHIP subtypes (DNMT3A, TET2, ASXL1), large CHIP (VAF ≥10%), inflammatory and cardiac biomarkers (high-sensitivity C-reactive protein, interleukin 6 [IL-6], IL-18, high-sensitivity troponin T [hs-TnT] and hs-TnI, N-terminal pro-B-type natriuretic peptide), and echocardiographic indices. Main Outcome Measure: Incident AF. Results: A total of 199 982 adults were included in this study. In ARIC participants (4131 [2.1%]; mean [SD] age, 76 [5] years; 2449 female [59%]; 1682 male [41%]; 935 Black [23%] and 3196 White [77%]), 1019 had any CHIP (24.7%), and 478 had large CHIP (11.6%). In UKB participants (195 851 [97.9%]; mean [SD] age, 56 [8] years; 108 370 female [55%]; 87 481 male [45%]; 3154 Black [2%], 183 747 White [94%], and 7971 other race [4%]), 11 328 had any CHIP (5.8%), and 5189 had large CHIP (2.6%). ARIC participants were followed up for a median (IQR) period of 7.0 (5.3-7.7) years, and UKB participants were followed up for a median (IQR) period of 12.2 (11.3-13.0) years. Meta-analyzed hazard ratios for AF were 1.12 (95% CI, 1.01-1.25; P = .04) for participants with vs without large CHIP, 1.29 (95% CI, 1.05-1.59; P = .02) for those with vs without large TET2 CHIP (seen in 1340 of 197 209 [0.67%]), and 1.45 (95% CI, 1.02-2.07; P = .04) for those with vs without large ASXL1 CHIP (seen in 314 of 197 209 [0.16%]). Large TET2 CHIP was associated with higher IL-6 levels. Additionally, large ASXL1 was associated with higher hs-TnT level and increased left ventricular mass index. Conclusions and Relevance: Large TET2 and ASXL1, but not DNMT3A, CHIP was associated with higher IL-6 level, indices of cardiac remodeling, and increased risk for AF. Future research is needed to elaborate on the mechanisms driving the associations and to investigate potential interventions to reduce the risk.

Multi-Ancestry Polygenic Risk Score for Coronary Heart Disease Based on an Ancestrally Diverse Genome-Wide Association Study and Population-Specific Optimization.

BACKGROUND: Predictive performance of polygenic risk scores (PRS) varies across populations. To facilitate equitable clinical use, we developed PRS for coronary heart disease (CHD; PRSCHD) for 5 genetic ancestry groups. METHODS: We derived ancestry-specific and multi-ancestry PRSCHD based on pruning and thresholding (PRSPT) and ancestry-based continuous shrinkage priors (PRSCSx) applied to summary statistics from the largest multi-ancestry genome-wide association study meta-analysis for CHD to date, including 1.1 million participants from 5 major genetic ancestry groups. Following training and optimization in the Million Veteran Program, we evaluated the best-performing PRSCHD in 176,988 individuals across 9 diverse cohorts. RESULTS: Multi-ancestry PRSPT and PRSCSx outperformed ancestry-specific PRSPT and PRSCSx across a range of tuning values. Two best-performing multi-ancestry PRSCHD (ie, PRSPTmult and PRSCSxmult) and 1 ancestry-specific (PRSCSxEUR) were taken forward for validation. PRSPTmult demonstrated the strongest association with CHD in individuals of South Asian ancestry and European ancestry (odds ratio per 1 SD [95% CI, 2.75 [2.41-3.14], 1.65 [1.59-1.72]), followed by East Asian ancestry (1.56 [1.50-1.61]), Hispanic/Latino ancestry (1.38 [1.24-1.54]), and African ancestry (1.16 [1.11-1.21]). PRSCSxmult showed the strongest associations in South Asian ancestry (2.67 [2.38-3.00]) and European ancestry (1.65 [1.59-1.71]), lower in East Asian ancestry (1.59 [1.54-1.64]), Hispanic/Latino ancestry (1.51 [1.35-1.69]), and the lowest in African ancestry (1.20 [1.15-1.26]). CONCLUSIONS: The use of summary statistics from a large multi-ancestry genome-wide meta-analysis improved the performance of PRSCHD in most ancestry groups compared with single-ancestry methods. Despite the use of one of the largest and most diverse sets of training and validation cohorts to date, improvement of predictive performance was limited in African ancestry. This highlights the need for larger genome-wide association study datasets of underrepresented populations to enhance the performance of PRSCHD.

Selection, optimization and validation of ten chronic disease polygenic risk scores for clinical implementation in diverse US populations.

Polygenic risk scores (PRSs) have improved in predictive performance, but several challenges remain to be addressed before PRSs can be implemented in the clinic, including reduced predictive performance of PRSs in diverse populations, and the interpretation and communication of genetic results to both providers and patients. To address these challenges, the National Human Genome Research Institute-funded Electronic Medical Records and Genomics (eMERGE) Network has developed a framework and pipeline for return of a PRS-based genome-informed risk assessment to 25,000 diverse adults and children as part of a clinical study. From an initial list of 23 conditions, ten were selected for implementation based on PRS performance, medical actionability and potential clinical utility, including cardiometabolic diseases and cancer. Standardized metrics were considered in the selection process, with additional consideration given to strength of evidence in African and Hispanic populations. We then developed a pipeline for clinical PRS implementation (score transfer to a clinical laboratory, validation and verification of score performance), and used genetic ancestry to calibrate PRS mean and variance, utilizing genetically diverse data from 13,475 participants of the All of Us Research Program cohort to train and test model parameters. Finally, we created a framework for regulatory compliance and developed a PRS clinical report for return to providers and for inclusion in an additional genome-informed risk assessment. The initial experience from eMERGE can inform the approach needed to implement PRS-based testing in diverse clinical settings.

Daylight Saving Time Practice and the Rate of Adverse Cardiovascular Events in the United States: A Probabilistic Assessment in a Large Nationwide Study.

We investigated the association of daylight saving time (DST) transitions with the rates of adverse cardiovascular events in a large, US-based nationwide study. The study cohort included 36,116,951 unique individuals from deidentified administrative claims data of the OptumLabs Data Warehouse. There were 74,722 total adverse cardiovascular events during DST transition and the control weeks (2 weeks before and after) in spring and autumn of 2015-2019. We used Bayesian hierarchical Poisson regression models to estimate event rate ratios representing the ratio of composite adverse cardiovascular event rates between DST transition and control weeks. There was an average increase of 3% (95% uncertainty interval, -3% to -10%) and 4% (95% uncertainty interval, -2% to -12%) in adverse cardiovascular event rates during Monday and Friday of the spring DST transition, respectively. The probability of this being associated with a moderate-to-large increase in the event rates (estimate event rate ratio, >1.10) was estimated to be less than 6% for Monday and Friday, and less than 1% for the remaining days. During autumn DST transition, the probability of any decrease in adverse cardiovascular event rates was estimated to be less than 46% and a moderate-to-large decrease in the event rates to be less than 4% across all days. Results were similar when adjusted by age. In conclusion, spring DST transition had a suggestive association with a minor increase in adverse cardiovascular event rates but with a very low estimated probability to be of clinical importance. Our findings suggest that DST transitions are unlikely to meaningfully impact the rate of cardiovascular events.

Genetic variation in the human leukocyte antigen region confers susceptibility to Clostridioides difficile infection.

Clostridioides difficile (C. diff.) infection (CDI) is a leading cause of hospital acquired diarrhea in North America and Europe and a major cause of morbidity and mortality. Known risk factors do not fully explain CDI susceptibility, and genetic susceptibility is suggested by the fact that some patients with colons that are colonized with C. diff. do not develop any infection while others develop severe or recurrent infections. To identify common genetic variants associated with CDI, we performed a genome-wide association analysis in 19,861 participants (1349 cases; 18,512 controls) from the Electronic Medical Records and Genomics (eMERGE) Network. Using logistic regression, we found strong evidence for genetic variation in the DRB locus of the MHC (HLA) II region that predisposes individuals to CDI (P > 1.0 × 10-14; OR 1.56). Altered transcriptional regulation in the HLA region may play a role in conferring susceptibility to this opportunistic enteric pathogen.

Genome-wide association meta-analysis identifies risk loci for abdominal aortic aneurysm and highlights PCSK9 as a therapeutic target.

Abdominal aortic aneurysm (AAA) is a common disease with substantial heritability. In this study, we performed a genome-wide association meta-analysis from 14 discovery cohorts and uncovered 141 independent associations, including 97 previously unreported loci. A polygenic risk score derived from meta-analysis explained AAA risk beyond clinical risk factors. Genes at AAA risk loci indicate involvement of lipid metabolism, vascular development and remodeling, extracellular matrix dysregulation and inflammation as key mechanisms in AAA pathogenesis. These genes also indicate overlap between the development of AAA and other monogenic aortopathies, particularly via transforming growth factor ß signaling. Motivated by the strong evidence for the role of lipid metabolism in AAA, we used Mendelian randomization to establish the central role of nonhigh-density lipoprotein cholesterol in AAA and identified the opportunity for repurposing of proprotein convertase, subtilisin/kexin-type 9 (PCSK9) inhibitors. This was supported by a study demonstrating that PCSK9 loss of function prevented the development of AAA in a preclinical mouse model.

A Multi-Ancestry Polygenic Risk Score for Coronary Heart Disease Based on an Ancestrally Diverse Genome-Wide Association Study and Population-Specific Optimization.

Background: Predictive performance of polygenic risk scores (PRS) varies across populations. To facilitate equitable clinical use, we developed PRS for coronary heart disease (PRSCHD) for 5 genetic ancestry groups. Methods: We derived ancestry-specific and multi-ancestry PRSCHD based on pruning and thresholding (PRSP+T) and continuous shrinkage priors (PRSCSx) applied on summary statistics from the largest multi-ancestry genome-wide meta-analysis for CHD to date, including 1.1 million participants from 5 continental populations. Following training and optimization of PRSCHD in the Million Veteran Program, we evaluated predictive performance of the best performing PRSCHD in 176,988 individuals across 9 cohorts of diverse genetic ancestry. Results: Multi-ancestry PRSP+T outperformed ancestry specific PRSP+T across a range of tuning values. In training stage, for all ancestry groups, PRSCSx performed better than PRSP+T and multi-ancestry PRS outperformed ancestry-specific PRS. In independent validation cohorts, the selected multi-ancestry PRSP+T demonstrated the strongest association with CHD in individuals of South Asian (SAS) and European (EUR) ancestry (OR per 1SD[95% CI]; 2.75[2.41-3.14], 1.65[1.59-1.72]), followed by East Asian (EAS) (1.56[1.50-1.61]), Hispanic/Latino (HIS) (1.38[1.24-1.54]), and weakest in African (AFR) ancestry (1.16[1.11-1.21]). The selected multi-ancestry PRSCSx showed stronger associacion with CHD in comparison within each ancestry group where the association was strongest in SAS (2.67[2.38-3.00]) and EUR (1.65[1.59-1.71]), progressively decreasing in EAS (1.59[1.54-1.64]), HIS (1.51[1.35-1.69]), and lowest in AFR (1.20[1.15-1.26]). Conclusions: Utilizing diverse summary statistics from a large multi-ancestry genome-wide meta-analysis led to improved performance of PRSCHD in most ancestry groups compared to single-ancestry methods. Improvement of predictive performance was limited, specifically in AFR and HIS, despite use of one of the largest and most diverse set of training and validation cohorts to date. This highlights the need for larger GWAS datasets of AFR and HIS individuals to enhance performance of PRSCHD.

Selection, optimization, and validation of ten chronic disease polygenic risk scores for clinical implementation in diverse populations.

Polygenic risk scores (PRS) have improved in predictive performance supporting their use in clinical practice. Reduced predictive performance of PRS in diverse populations can exacerbate existing health disparities. The NHGRI-funded eMERGE Network is returning a PRS-based genome-informed risk assessment to 25,000 diverse adults and children. We assessed PRS performance, medical actionability, and potential clinical utility for 23 conditions. Standardized metrics were considered in the selection process with additional consideration given to strength of evidence in African and Hispanic populations. Ten conditions were selected with a range of high-risk thresholds: atrial fibrillation, breast cancer, chronic kidney disease, coronary heart disease, hypercholesterolemia, prostate cancer, asthma, type 1 diabetes, obesity, and type 2 diabetes. We developed a pipeline for clinical PRS implementation, used genetic ancestry to calibrate PRS mean and variance, created a framework for regulatory compliance, and developed a PRS clinical report. eMERGE's experience informs the infrastructure needed to implement PRS-based implementation in diverse clinical settings.

Evidence of epistasis in regions of long-range linkage disequilibrium across five complex diseases in the UK Biobank and eMERGE datasets.

Leveraging linkage disequilibrium (LD) patterns as representative of population substructure enables the discovery of additive association signals in genome-wide association studies (GWASs). Standard GWASs are well-powered to interrogate additive models; however, new approaches are required for invesigating other modes of inheritance such as dominance and epistasis. Epistasis, or non-additive interaction between genes, exists across the genome but often goes undetected because of a lack of statistical power. Furthermore, the adoption of LD pruning as customary in standard GWASs excludes detection of sites that are in LD but might underlie the genetic architecture of complex traits. We hypothesize that uncovering long-range interactions between loci with strong LD due to epistatic selection can elucidate genetic mechanisms underlying common diseases. To investigate this hypothesis, we tested for associations between 23 common diseases and 5,625,845 epistatic SNP-SNP pairs (determined by Ohta's D statistics) in long-range LD (>0.25 cM). Across five disease phenotypes, we identified one significant and four near-significant associations that replicated in two large genotype-phenotype datasets (UK Biobank and eMERGE). The genes that were most likely involved in the replicated associations were (1) members of highly conserved gene families with complex roles in multiple pathways, (2) essential genes, and/or (3) genes that were associated in the literature with complex traits that display variable expressivity. These results support the highly pleiotropic and conserved nature of variants in long-range LD under epistatic selection. Our work supports the hypothesis that epistatic interactions regulate diverse clinical mechanisms and might especially be driving factors in conditions with a wide range of phenotypic outcomes.

Familial Hypercholesterolemia in the Electronic Medical Records and Genomics Network: Prevalence, Penetrance, Cardiovascular Risk, and Outcomes After Return of Results.

BACKGROUND: The implications of secondary findings detected in large-scale sequencing projects remain uncertain. We assessed prevalence and penetrance of pathogenic familial hypercholesterolemia (FH) variants, their association with coronary heart disease (CHD), and 1-year outcomes following return of results in phase III of the electronic medical records and genomics network. METHODS: Adult participants (n=18 544) at 7 sites were enrolled in a prospective cohort study to assess the clinical impact of returning results from targeted sequencing of 68 actionable genes, including LDLR, APOB, and PCSK9. FH variant prevalence and penetrance (defined as low-density lipoprotein cholesterol >155 mg/dL) were estimated after excluding participants enrolled on the basis of hypercholesterolemia. Multivariable logistic regression was used to estimate the odds of CHD compared to age- and sex-matched controls without FH-associated variants. Process (eg, referral to a specialist or ordering new tests), intermediate (eg, new diagnosis of FH), and clinical (eg, treatment modification) outcomes within 1 year after return of results were ascertained by electronic health record review. RESULTS: The prevalence of FH-associated pathogenic variants was 1 in 188 (69 of 13,019 unselected participants). Penetrance was 87.5%. The presence of an FH variant was associated with CHD (odds ratio, 3.02 [2.00-4.53]) and premature CHD (odds ratio, 3.68 [2.34-5.78]). At least 1 outcome occurred in 92% of participants; 44% received a new diagnosis of FH and 26% had treatment modified following return of results. CONCLUSIONS: In a multisite cohort of electronic health record-linked biobanks, monogenic FH was prevalent, penetrant, and associated with presence of CHD. Nearly half of participants with an FH-associated variant received a new diagnosis of FH and a quarter had treatment modified after return of results. These results highlight the potential utility of sequencing electronic health record-linked biobanks to detect FH.

Evaluation of the portability of computable phenotypes with natural language processing in the eMERGE network.

The electronic Medical Records and Genomics (eMERGE) Network assessed the feasibility of deploying portable phenotype rule-based algorithms with natural language processing (NLP) components added to improve performance of existing algorithms using electronic health records (EHRs). Based on scientific merit and predicted difficulty, eMERGE selected six existing phenotypes to enhance with NLP. We assessed performance, portability, and ease of use. We summarized lessons learned by: (1) challenges; (2) best practices to address challenges based on existing evidence and/or eMERGE experience; and (3) opportunities for future research. Adding NLP resulted in improved, or the same, precision and/or recall for all but one algorithm. Portability, phenotyping workflow/process, and technology were major themes. With NLP, development and validation took longer. Besides portability of NLP technology and algorithm replicability, factors to ensure success include privacy protection, technical infrastructure setup, intellectual property agreement, and efficient communication. Workflow improvements can improve communication and reduce implementation time. NLP performance varied mainly due to clinical document heterogeneity; therefore, we suggest using semi-structured notes, comprehensive documentation, and customization options. NLP portability is possible with improved phenotype algorithm performance, but careful planning and architecture of the algorithms is essential to support local customizations.

Genetic Predictors of Blood Pressure Traits are Associated with Preeclampsia.

Background: Preeclampsia, a pregnancy complication characterized by hypertension after 20 gestational weeks, is a major cause of maternal and neonatal morbidity and mortality. The mechanisms leading to preeclampsia are unclear; however, there is evidence that preeclampsia is highly heritable. We evaluated the association of polygenic risk scores (PRS) for blood pressure traits and preeclampsia to assess whether there is shared genetic architecture. Methods: Participants were obtained from Vanderbilt University's BioVU, the Electronic Medical Records and Genomics network, and the Penn Medicine Biobank. Non-Hispanic Black and White females of reproductive age with indications of pregnancy and genotype information were included. Preeclampsia was defined by ICD codes. Summary statistics for diastolic blood pressure (DBP), systolic blood pressure (SBP), and pulse pressure (PP) PRS were obtained from Giri et al 2019. Associations between preeclampsia and each PRS were evaluated separately by race and study population before evidence was meta-analyzed. Prediction models were developed and evaluated using 10-fold cross validation. Results: In the 3,504 Black and 5,009 White individuals included, the rate of preeclampsia was 15.49%. The DBP and SBP PRSs were associated with preeclampsia in Whites but not Blacks. The PP PRS was significantly associated with preeclampsia in Blacks and Whites. In trans-ancestry meta-analysis, all PRSs were associated with preeclampsia (OR DBP =1.10, 95% CI=1.02-1.17, p =7.68×10 -3 ; OR SBP =1.16, 95% CI=1.09-1.23, p =2.23×10 -6 ; OR PP =1.14, 95% CI=1.07-1.27, p =9.86×10 -5 ). However, addition of PRSs to clinical prediction models did not improve predictive performance. Conclusions: Genetic factors contributing to blood pressure regulation in the general population also predispose to preeclampsia.

Returning integrated genomic risk and clinical recommendations: The eMERGE study.

PURPOSE: Assessing the risk of common, complex diseases requires consideration of clinical risk factors as well as monogenic and polygenic risks, which in turn may be reflected in family history. Returning risks to individuals and providers may influence preventive care or use of prophylactic therapies for those individuals at high genetic risk. METHODS: To enable integrated genetic risk assessment, the eMERGE (electronic MEdical Records and GEnomics) network is enrolling 25,000 diverse individuals in a prospective cohort study across 10 sites. The network developed methods to return cross-ancestry polygenic risk scores, monogenic risks, family history, and clinical risk assessments via a genome-informed risk assessment (GIRA) report and will assess uptake of care recommendations after return of results. RESULTS: GIRAs include summary care recommendations for 11 conditions, education pages, and clinical laboratory reports. The return of high-risk GIRA to individuals and providers includes guidelines for care and lifestyle recommendations. Assembling the GIRA required infrastructure and workflows for ingesting and presenting content from multiple sources. Recruitment began in February 2022. CONCLUSION: Return of a novel report for communicating monogenic, polygenic, and family history-based risk factors will inform the benefits of integrated genetic risk assessment for routine health care.

Quantifying factors that affect polygenic risk score performance across diverse ancestries and age groups for body mass index.

Polygenic risk scores (PRS) have led to enthusiasm for precision medicine. However, it is well documented that PRS do not generalize across groups differing in ancestry or sample characteristics e.g., age. Quantifying performance of PRS across different groups of study participants, using genome-wide association study (GWAS) summary statistics from multiple ancestry groups and sample sizes, and using different linkage disequilibrium (LD) reference panels may clarify which factors are limiting PRS transferability. To evaluate these factors in the PRS generation process, we generated body mass index (BMI) PRS (PRSBMI) in the Electronic Medical Records and Genomics (eMERGE) network (N=75,661). Analyses were conducted in two ancestry groups (European and African) and three age ranges (adult, teenagers, and children). For PRSBMI calculations, we evaluated five LD reference panels and three sets of GWAS summary statistics of varying sample size and ancestry. PRSBMI performance increased for both African and European ancestry individuals using cross-ancestry GWAS summary statistics compared to European-only summary statistics (6.3% and 3.7% relative R2 increase, respectively, pAfrican=0.038, pEuropean=6.26x10-4). The effects of LD reference panels were more pronounced in African ancestry study datasets. PRSBMI performance degraded in children; R2 was less than half of teenagers or adults. The effect of GWAS summary statistics sample size was small when modeled with the other factors. Additionally, the potential of using a PRS generated for one trait to predict risk for comorbid diseases is not well understood especially in the context of cross-ancestry analyses - we explored clinical comorbidities from the electronic health record associated with PRSBMI and identified significant associations with type 2 diabetes and coronary atherosclerosis. In summary, this study quantifies the effects that ancestry, GWAS summary statistic sample size, and LD reference panel have on PRS performance, especially in cross-ancestry and age-specific analyses.

Polygenic Risk, Rare Variants, and Family History: Independent and Additive Effects on Coronary Heart Disease.

Background: Genetic factors are not included in prediction models for coronary heart disease (CHD). Objectives: The authors assessed the predictive utility of a polygenic risk score (PRS) for CHD (defined as myocardial infarction, coronary revascularization, or cardiovascular death) and whether the risks due to monogenic familial hypercholesterolemia (FH) and family history (FamHx) are independent of and additive to the PRS. Methods: In UK-biobank participants, PRSCHD was calculated using metaGRS, and 10-year risk for incident CHD was estimated using the pooled cohort equations (PCE). The area under the curve (AUC) of the receiver operator curve and net reclassification improvement (NRI) were assessed. FH was defined as the presence of a pathogenic or likely pathogenic variant in LDLR, APOB, or PCSK9. FamHx was defined as a diagnosis of CHD in first-degree relatives. Independent and additive effects of PRSCHD, FH, and FamHx were evaluated in stratified analyses. Results: In 323,373 participants with genotype data, the addition of PRSCHD to PCE increased the AUC from 0.759 (95% CI: 0.755-0.763) to 0.773 (95% CI: 0.769-0.777). The AUC and NRIEvent for PRSCHD were higher before the age of 55 years. Of 199,997 participants with exome sequence data, 10,000 had a PRSCHD ≥95th percentile (PRSP95), 673 had FH, and 46,163 had FamHx. The CHD risk associated with PRSP95 was independent of FH and FamHx. The risks associated with combinations of PRSCHD, FH, and FamHx were additive and comprehensive estimates could be obtained by multiplying the risk from each genetic factor. Conclusions: Incorporating PRSCHD into the PCE improves risk prediction for CHD, especially at younger ages. The associations of PRSCHD, FH, and FamHx with CHD were independent and additive.

Genome-wide association and multi-trait analyses characterize the common genetic architecture of heart failure.

Heart failure is a leading cause of cardiovascular morbidity and mortality. However, the contribution of common genetic variation to heart failure risk has not been fully elucidated, particularly in comparison to other common cardiometabolic traits. We report a multi-ancestry genome-wide association study meta-analysis of all-cause heart failure including up to 115,150 cases and 1,550,331 controls of diverse genetic ancestry, identifying 47 risk loci. We also perform multivariate genome-wide association studies that integrate heart failure with related cardiac magnetic resonance imaging endophenotypes, identifying 61 risk loci. Gene-prioritization analyses including colocalization and transcriptome-wide association studies identify known and previously unreported candidate cardiomyopathy genes and cellular processes, which we validate in gene-expression profiling of failing and healthy human hearts. Colocalization, gene expression profiling, and Mendelian randomization provide convergent evidence for the roles of BCKDHA and circulating branch-chain amino acids in heart failure and cardiac structure. Finally, proteome-wide Mendelian randomization identifies 9 circulating proteins associated with heart failure or quantitative imaging traits. These analyses highlight similarities and differences among heart failure and associated cardiovascular imaging endophenotypes, implicate common genetic variation in the pathogenesis of heart failure, and identify circulating proteins that may represent cardiomyopathy treatment targets.

Large-scale genome-wide association study of coronary artery disease in genetically diverse populations.

We report a genome-wide association study (GWAS) of coronary artery disease (CAD) incorporating nearly a quarter of a million cases, in which existing studies are integrated with data from cohorts of white, Black and Hispanic individuals from the Million Veteran Program. We document near equivalent heritability of CAD across multiple ancestral groups, identify 95 novel loci, including nine on the X chromosome, detect eight loci of genome-wide significance in Black and Hispanic individuals, and demonstrate that two common haplotypes at the 9p21 locus are responsible for risk stratification in all populations except those of African origin, in which these haplotypes are virtually absent. Moreover, in the largest GWAS for angiographically derived coronary atherosclerosis performed to date, we find 15 loci of genome-wide significance that robustly overlap with established loci for clinical CAD. Phenome-wide association analyses of novel loci and polygenic risk scores (PRSs) augment signals related to insulin resistance, extend pleiotropic associations of these loci to include smoking and family history, and precisely document the markedly reduced transferability of existing PRSs to Black individuals. Downstream integrative analyses reinforce the critical roles of vascular endothelial, fibroblast, and smooth muscle cells in CAD susceptibility, but also point to a shared biology between atherosclerosis and oncogenesis. This study highlights the value of diverse populations in further characterizing the genetic architecture of CAD.

Use of Polygenic Risk Scores for Coronary Heart Disease in Ancestrally Diverse Populations.

PURPOSE OF REVIEW: A polygenic risk score (PRS) is a measure of genetic liability to a disease and is typically normally distributed in a population. Individuals in the upper tail of this distribution often have relative risk equivalent to that of monogenic form of the disease. The majority of currently available PRSs for coronary heart disease (CHD) have been generated from cohorts of European ancestry (EUR) and vary in their applicability to other ancestry groups. In this report, we review the performance of PRSs for CHD across different ancestries and efforts to reduce variability in performance including novel population and statistical genetics approaches. RECENT FINDINGS: PRSs for CHD perform robustly in EUR populations but lag in performance in non-EUR groups, particularly individuals of African ancestry. Several large consortia have been established to enable genomic studies in diverse ancestry groups and develop methods to improve PRS performance in multi-ancestry contexts as well as admixed individuals. These include fine-mapping to ascertain causal variants, trans ancestry meta-analyses, and ancestry deconvolution in admixed individuals. PRSs are being used in the clinical setting but enthusiasm has been tempered by the variable performance in non-EUR ancestry groups. Increasing diversity in genomic association studies and continued innovation in methodological approaches are needed to improve PRS performance in non-EUR individuals for equitable implementation of genomic medicine.

Genome-wide polygenic score to predict chronic kidney disease across ancestries.

Chronic kidney disease (CKD) is a common complex condition associated with high morbidity and mortality. Polygenic prediction could enhance CKD screening and prevention; however, this approach has not been optimized for ancestrally diverse populations. By combining APOL1 risk genotypes with genome-wide association studies (GWAS) of kidney function, we designed, optimized and validated a genome-wide polygenic score (GPS) for CKD. The new GPS was tested in 15 independent cohorts, including 3 cohorts of European ancestry (n = 97,050), 6 cohorts of African ancestry (n = 14,544), 4 cohorts of Asian ancestry (n = 8,625) and 2 admixed Latinx cohorts (n = 3,625). We demonstrated score transferability with reproducible performance across all tested cohorts. The top 2% of the GPS was associated with nearly threefold increased risk of CKD across ancestries. In African ancestry cohorts, the APOL1 risk genotype and polygenic component of the GPS had additive effects on the risk of CKD.