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Supplemental Digital Content is available in the text., Background: Abdominal aortic aneurysm (AAA) is an important cause of cardiovascular mortality; however, its genetic determinants remain incompletely defined. In total, 10 previously identified risk loci explain a small fraction of AAA heritability. Methods: We performed a genome-wide association study in the Million Veteran Program testing ≈18 million DNA sequence variants with AAA (7642 cases and 172 172 controls) in veterans of European ancestry with independent replication in up to 4972 cases and 99 858 controls. We then used mendelian randomization to examine the causal effects of blood pressure on AAA. We examined the association of AAA risk variants with aneurysms in the lower extremity, cerebral, and iliac arterial beds, and derived a genome-wide polygenic risk score (PRS) to identify a subset of the population at greater risk for disease. Results: Through a genome-wide association study, we identified 14 novel loci, bringing the total number of known significant AAA loci to 24. In our mendelian randomization analysis, we demonstrate that a genetic increase of 10 mm Hg in diastolic blood pressure (odds ratio, 1.43 [95% CI, 1.24–1.66]; P=1.6×10−6), as opposed to systolic blood pressure (odds ratio, 1.06 [95% CI, 0.97–1.15]; P=0.2), likely has a causal relationship with AAA development. We observed that 19 of 24 AAA risk variants associate with aneurysms in at least 1 other vascular territory. A 29-variant PRS was strongly associated with AAA (odds ratioPRS, 1.26 [95% CI, 1.18–1.36]; PPRS=2.7×10−11 per SD increase in PRS), independent of family history and smoking risk factors (odds ratioPRS+family history+smoking, 1.24 [95% CI, 1.14–1.35]; PPRS=1.27×10−6). Using this PRS, we identified a subset of the population with AAA prevalence greater than that observed in screening trials informing current guidelines. Conclusions: We identify novel AAA genetic associations with therapeutic implications and identify a subset of the population at significantly increased genetic risk of AAA independent of family history. Our data suggest that extending current screening guidelines to include testing to identify those with high polygenic AAA risk, once the cost of genotyping becomes comparable with that of screening ultrasound, would significantly increase the yield of current screening at reasonable cost.

Importance Multiple polygenic risk scores (PRSs) for breast cancer have been developed from large research consortia; however, their generalizability to diverse clinical settings is unknown. Objective To examine the performance of previously developed breast cancer PRSs in a clinical setting for women of European, African, and Latinx ancestry. Design, Setting, and Participants This cohort study using the Electronic Medical Records and Genomics (eMERGE) network data set included 39 591 women from 9 contributing medical centers in the US that had electronic medical records (EMR) linked to genotype data. Breast cancer cases and controls were identified through a validated EMR phenotyping algorithm. Main Outcomes and Measures Multivariable logistic regression was used to assess the association between breast cancer risk and 7 previously developed PRSs, adjusting for age, study site, breast cancer family history, and first 3 ancestry informative principal components. Results This study included 39 591 women: 33 594 with European, 3801 with African, and 2196 with Latinx ancestry. The mean (SD) age at breast cancer diagnosis was 60.7 (13.0), 58.8 (12.5), and 60.1 (13.0) years for women with European, African, and Latinx ancestry, respectively. PRSs derived from women with European ancestry were associated with breast cancer risk in women with European ancestry (highest odds ratio [OR] per 1-SD increase, 1.46; 95% CI, 1.41-1.51), women with Latinx ancestry (highest OR, 1.31; 95% CI, 1.09-1.58), and women with African ancestry (OR, 1.19; 95% CI, 1.05-1.35). For women with European ancestry, this association with breast cancer risk was largest in the extremes of the PRS distribution, with ORs ranging from 2.19 (95% CI, 1.84-2.53) to 2.48 (95% CI, 1.89-3.25) for the 3 different PRSs examined for those in the highest 1% of the PRS compared with those in the middle quantile. Among women with Latinx and African ancestries at the extremes of the PRS distribution, there were no statistically significant associations. Conclusions and Relevance This cohort study found that PRS models derived from women with European ancestry for breast cancer risk generalized well for women with European, Latinx, and African ancestries across different clinical settings, although the effect sizes for women with African ancestry were smaller, likely because of differences in risk allele frequencies and linkage disequilibrium patterns. These results highlight the need to improve representation of diverse population groups, particularly women with African ancestry, in genomic research cohorts.

Background: Sequencing Mendelian arrhythmia genes in individuals without an indication for arrhythmia genetic testing can identify carriers of pathogenic or likely pathogenic (P/LP) variants. However, the extent to which these variants are associated with clinically meaningful phenotypes before or after return of variant results is unclear. In addition, the majority of discovered variants are currently classified as variants of uncertain significance, limiting clinical actionability. Methods: The eMERGE-III study (Electronic Medical Records and Genomics Phase III) is a multicenter prospective cohort that included 21 846 participants without previous indication for cardiac genetic testing. Participants were sequenced for 109 Mendelian disease genes, including 10 linked to arrhythmia syndromes. Variant carriers were assessed with electronic health record–derived phenotypes and follow-up clinical examination. Selected variants of uncertain significance (n=50) were characterized in vitro with automated electrophysiology experiments in HEK293 cells. Results: As previously reported, 3.0% of participants had P/LP variants in the 109 genes. Herein, we report 120 participants (0.6%) with P/LP arrhythmia variants. Compared with noncarriers, arrhythmia P/LP carriers had a significantly higher burden of arrhythmia phenotypes in their electronic health records. Fifty-four participants had variant results returned. Nineteen of these 54 participants had inherited arrhythmia syndrome diagnoses (primarily long-QT syndrome), and 12 of these 19 diagnoses were made only after variant results were returned (0.05%). After in vitro functional evaluation of 50 variants of uncertain significance, we reclassified 11 variants: 3 to likely benign and 8 to P/LP. Conclusions: Genome sequencing in a large population without indication for arrhythmia genetic testing identified phenotype-positive carriers of variants in congenital arrhythmia syndrome disease genes. As the genomes of large numbers of people are sequenced, the disease risk from rare variants in arrhythmia genes can be assessed by integrating genomic screening, electronic health record phenotypes, and in vitro functional studies. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier; NCT03394859.

The coronavirus disease 2019 (COVID-19) pandemic continues its global spread. Coordinated effort on a vast scale is required to halt its progression and to save lives. Electronic health record (EHR) data are a valuable resource to mitigate the COVID-19 pandemic. We review how the EHR could be used for disease surveillance and contact tracing. When linked to "omics" data, the EHR could facilitate identification of genetic susceptibility variants, leading to insights into risk factors, disease complications, and drug repurposing. Real-time monitoring of patients could enable early detection of potential complications, informing appropriate interventions and therapy. We reviewed relevant articles from PubMed, MEDLINE, and Google Scholar searches as well as preprint servers, given the rapidly evolving understanding of the COVID-19 pandemic.

We investigated monogenic and polygenic causes of hypercholesterolemia in a population-based cohort, excluding secondary hypercholesterolemia, and using an established framework to identify pathogenic variants. We studied 1682 individuals (50.2 ± 8.6 years, 41.3% males) from southeast Minnesota with primary hypercholesterolemia (low-density lipoprotein cholesterol (LDL-C) ≥155 mg/dl in the absence of identifiable secondary causes). Familial hypercholesterolemia (FH) phenotype was defined as a Dutch Lipid Clinic Network (DLCN) score ≥6. Participants underwent sequencing of LDLR, APOB, and PCSK9, and genotyping of 12 LDL-C-associated single-nucleotide variants to construct a polygenic score (PGS) for LDL-C. The presence of a pathogenic/likely pathogenic variant was considered monogenic etiology and a PGS ≥90th percentile was considered polygenic etiology. The mean LDL-C level was 187.3 ± 32.3 mg/dl and phenotypic FH was present in 8.4% of the cohort. An identifiable genetic etiology was present in 17.1% individuals (monogenic in 1.5% and polygenic in 15.6%). Phenotypic and genetic FH showed poor overlap. Only 26% of those who met the clinical criteria of FH had an identifiable genetic etiology and of those with an identifiable genetic etiology only 12.9% met clinical criteria for FH. Genetic factors explained 7.4% of the variance in LDL-C. In conclusion, in adults with primary hypercholesterolemia, 17.1% had an identifiable genetic etiology and the overlap between phenotypic and genetic FH was modest.

Coronary artery disease (CAD) is a leading cause of death, yet its genetic determinants are not fully elucidated. We report a multi-ethnic genome-wide association study of CAD involving nearly a quarter of a million cases, incorporating the largest cohorts to date of Whites, Blacks, and Hispanics from the Million Veteran Program with existing studies including CARDIoGRAMplusC4D, UK Biobank, and Biobank Japan. We verify substantial and nearly equivalent heritability of CAD across multiple ancestral groups, discover 107 novel loci including the first nine on the X-chromosome, identify the first eight genome-wide significant loci among Blacks and Hispanics, and demonstrate that two common haplotypes are largely responsible for the risk stratification at the well-known 9p21 locus in most populations except those of African origin where both haplotypes are virtually absent. We identify 15 loci for angiographically derived burden of coronary atherosclerosis, which robustly overlap with the strongest and earliest loci reported to date for clinical CAD. Phenome-wide association analyses of novel loci and externally validated polygenic risk scores (PRS) augment signals from the insulin resistance cluster of risk factors and consequences, extend previously established pleiotropic associations of loci with traditional risk factors to include smoking and family history, and confirm a substantially reduced transferability of existing PRS to Blacks. Downstream integrative genomic analyses reinforce the critical role of endothelial, fibroblast, and smooth muscle cells within the coronary vessel wall in CAD susceptibility. Our study highlights the value of a multi-ethnic design in efficiently characterizing the genetic architecture of CAD across all human populations.

Introduction: Several clinical trials evaluating the efficacy of a carotid revascularization procedure excluded patients above age 80. In the current study, we sought to assess the differences in characteristics of octogenarians undergoing carotid endarterectomy (CEA) and carotid artery stenting (CAS) for carotid stenosis using “real-world” data from a national surgical quality registry. Methods: The National Surgical Quality Improvement Program (NSQIP) targeted datasets for CEA and CAS were queried for patients aged ≥80 years between 2012-2018. Results: We identified 5,814 patients undergoing CEA and 189 patients undergoing CAS. Patients in the CAS group were more likely to be ≥90 years (p=0.004), diabetic (p=0.04), had a history of CHF (p=0.012) and a bleeding-disorder (p80%-100%) of the ipsilateral carotid, while 13(14.5%) in the CAS group and 302 (11%) in the CEA group had severe or total stenosis of contralateral carotid. Among symptomatic patients, 58(61.7%) in the CAS group and 1527 (57.5%) in the CEA group were found to have severe/total stenosis of the ipsilateral-carotid, while 12(12.8%) in the CAS group and 208(7.8%) in the CEA group were found to have severe/total occlusion of the contralateral carotid. In the carotid endarterectomy group, 12.2% (n=711) underwent CEA-alone, 44.3% (n=2,575) CEA with angioplasty, 29.9% (n=1,737) CEA with angioplasty and shunt, 2.9% (n=166) CEA with shunt and 10.7%(n=166) eversion CEA. In the CAS group, 52.4%(n=99) underwent CAS with a single tapered stent, 29.1%(n=55) CAS with single tapered stent with CPD, 11.1%(n=21) single straight stent with CPD and 1.6%(n=3) a single straight stent alone. Conclusion: These analyses from real-world data show that there may be some differences in demographic and comorbid characteristics between octogenarians undergoing CAS and CEA.

Introduction: Due to their exclusion from most clinical trials, outcomes of carotid revascularization via a carotid endarterectomy (CEA) or carotid artery stenting (CAS) among octogenarians are not well studied. Herein, we present analysis of thirty-day stroke and mortality of patients aged ≥ 80 using real-world data from a national surgical quality registry. Methods: The National Surgical Quality Improvement Program (NSQIP) targeted dataset for CEA and CAS was queried for patients aged ≥ 80 undergoing CEA and CAS between 2012-2018. Results: A total of 94 and 2,656 patients aged ≥ 80 with symptomatic carotid stenosis undergoing CAS and CEA (respectively) were identified. Patients in the CAS group were more likely to be over 90 (p=0.006). Patients in the CAS group were more likely to have high-risk anatomy (p Conclusion: Real world analysis from a surgical quality registry show that both CAS and CEA are associated with optimal 30-day outcomes among octogenarians with symptomatic carotid stenosis.

Background: The pathophysiology of lipoprotein (a) [Lp(a)] remains obscure. We conducted a phenome wide analysis study (PheWAS) to identify pleiotropic effects of LPA variants. Methods: Among 51,843 European-ancestry participants (age 58±16 years, 54% female) of the electronic MEdical Records and Genomics (eMERGE) network we assessed whether LPA variants exhibited pleiotropic affects through an electronic health record-based PheWAS. We adjusted significant associations by presence of atherosclerotic cardiovascular disease (ASCVD; defined as a composite of coronary heart disease, cerebrovascular disease, and peripheral artery disease) to determine whether those associations were independent of ASCVD. Results: In PheWAS analysis, we tested 864 phecodes with 36 independent LPA variants. We identified 21 significant associations with non-ASCVD phenotypes including heart failure, aortic valve stenosis, and chronic kidney disease of which 14 were replicated across independent cohorts. The strength of associations between the LPA variant rs10455872 and both heart failure and aortic valve stenosis related phecodes were significantly attenuated after adjustment for ASCVD. However, the association with chronic kidney disease phecode remained independent following adjustment for ASCVD without any attenuation in the estimated odds ratio (Table). Conclusions: LPA genetic variants were associated with aortic valve stenosis, heart failure and chronic kidney disease. The observed association of LPA variant rs10455872 with aortic stenosis and heart failure appear to be partially mediated by ASCVD, while the association with chronic kidney disease appears to be independent of ASCVD. Additional studies are needed to elucidate potential mechanisms by which Lp(a) may contribute to the pathogenesis of non-ASCVD disease phenotypes.

Background: Return of incidental genetic findings is recommended for pathogenic/likely pathogenic (P/LP) variants in Mendelian arrhythmia genes. The extent to which these variants are associated with arrhythmia phenotypes in unselected populations is unknown. Objective: Assess the impact of return of results (RoR) of P/LP variants in 4 arrhythmia genes in research participants not selected for cardiovascular disease. Methods: The cohort included 24,410 participants from the Electronic Medical Records and Genomics Network. Rare variants (minor allele frequency KCNE1 , KCNH2 , KCNQ1 , and SCN5A were identified and classified according to ACMG guidelines. Arrhythmia phenotypes extracted from electronic health records (EHRs) included atrial fibrillation/flutter (AF/AFL), conduction system disease, long QT syndrome (LQTS), ventricular tachycardia/fibrillation (VT/VF), and premature ventricular contractions (PVCs). P/LP carriers’ phenotypes were compared to non-carriers using logistic regression adjusted for demographic covariates and site. Participants with P/LP variants were informed of their results and the impact of this RoR was assessed after 1 year of follow-up clinical care. Results: The participants included 53.7% females and 72.5% white individuals, with a median age of 57 years. 71 participants had a heterozygous P/LP variant in one of the 4 genes. LQTS diagnoses were associated with P/LP carrier status for all 4 genes ( KCNE1 OR 22.8, p=1.0e-4; KCNH2 OR 35.1, p=1.8e-7; KCNQ1 OR 27.3, p=3.6e-18; SCN5A OR 5.6, p=0.02). Carriers of SCN5A P/LP variants were also more likely to have PVCs (OR 4.3, p=0.003). Sensitivity analyses showed the associations predated the RoR. EHRs included a diagnosis of LQTS or Brugada Syndrome in 11/71 (16%) pre-RoR, and 16 more were diagnosed after RoR (27/71, 38%). A total of 47/71 (66%) participants had a documented arrhythmia phenotype 1 year after RoR, although 20 of these participants were not diagnosed with an inherited arrhythmia syndrome. Conclusion: Inherited arrhythmia diagnoses could be established in nearly half of participants with P/LP variants. These data indicate that return of incidental P/LP variants in these genes may facilitate the early diagnosis of arrhythmias.

Introduction Fibromuscular dysplasia (FMD) is a non-atherosclerotic arteriopathy of unknown etiology, affecting mostly middle-aged women. It is characterized by stenotic lesions of the vascular wall in middle-size arteries, sometimes associated with dissection, aneurysm or tortuosity. Objective We aim at identifying genetic causes of FMD to better understand its mechanism and relation with other vasculopathies. Methods We report results from the first genome-wide association meta-analysis of six studies including 1962 FMD cases and 7100 controls. We integrated genetic association with arterial gene expression using transcriptome-wide association analysis. To identify FMD associated variants located in regulatory elements, we determined open chromatin regions in artery-derived primary cells using ATAC-Seq and estimated heritability and genetic correlation of FMD with other vascular traits and diseases using LD Score regression. Results We found an estimate of SNP-based heritability compatible with a polygenic feature for FMD and report four robustly associated loci (PHACTR1, LRP1, ATP2B1, and LIMA1). Transcriptome-wide association analysis in arteries identified one additional locus (SLC24A3). We found that FMD associated variants were located in arterial-specific regulatory elements. Target genes were broadly involved in mechanisms related to actin cytoskeleton and intracellular calcium homeostasis, central to vascular contraction. We found significant genetic overlap between FMD and blood pressure, although hypertension was not confounding the genetic association with FMD. We also report an important genetic overlap with migraine, intracranial aneurysm, coronary artery disease and LDL cholesterol. Conclusion We identified several loci related to vascular contraction, suggesting that altered vascular tonicity may play a role in the pathogenesis of FMD. We find that FMD is genetically close to several vascular diseases where vascular integrity is impaired.

Fibromuscular dysplasia (FMD) is an arteriopathy that presents clinically by hypertension and stroke, mostly in early middle-aged women. We report results from the first genome-wide association meta-analysis of FMD including 1962 FMD cases and 7100 controls. We confirmedPHACTR1and identified three new loci (LRP1, ATP2B1, andLIMA1)associated with FMD. Transcriptome-wide association analysis in arteries identified one additional locus (SLC24A3). FMD associated variants were located in arterial-specific enhancers active in vascular smooth muscle cells and fibroblasts. Target genes are broadly involved in mechanisms related to actin cytoskeleton and intracellular calcium homeostasis, central to vascular contraction. Cross-trait linkage disequilibrium analyses identified positive genetic correlations with blood pressure, migraine and intracranial aneurysm, and an inverse correlation with coronary artery disease, independent from the genetics of blood pressure.

BackgroundThe majority of polygenic risk scores (PRS) for breast cancer have been developed and validated using cohorts of European ancestry (EA). Less is known about the generalizability of these PRS in other ancestral groups.MethodsThe Electronic Medical Records and Genomics (eMERGE) network cohort dataset was used to evaluate the performance of seven previously developed PRS (three EA-based PRSs, and four non-EA based PRSs) in three major ancestral groups. Each PRS was separately evaluated in EA (cases: 3939; controls: 28840), African ancestry (AA) (cases: 121; controls: 1173) and self-reported LatinX ancestry (LA) (cases: 92; controls: 1363) women. We assessed the association between breast cancer risk and each PRS, adjusting forage, study site, breast cancer family history, and first three ancestry informative principal components.ResultsEA-based PRSs were significantly associated with breast cancer risk in EA women per one SD increase (odds ratio [OR] = 1.45, 95% confidence interval [CI] = 1.40–1.51), and LA women (OR = 1.41, 95% CI = 1.13–1.77), but not AA women (OR = 1.13, 95% CI = 0.92–1.40). There was no statistically significant association for the non-EA PRSs in all ancestry groups, LA including an LA-based PRS and an AA-based PRS.ConclusionWe evaluated EA-derived PRS for estimating breast cancer risk using the eMERGE dataset and found they generalized well in LA women but not in AA women. For non-EA based PRSs, we did not replicate previously reported associations for the respective ancestries in the eMERGE cohort. Our results highlight the need to improve representation of diverse population groups, particularly AA women, in research cohorts.

Electronic health record (EHR)-based clinical decision support (CDS) can address the low awareness and undertreatment of familial hypercholesterolemia (FH), a disorder associated with a markedly increased risk of coronary heart disease. We aimed to incorporate provider perspectives into the development and implementation of a CDS tool for FH. An implementation science framework and a user-centered design process were used to create a CDS tool for FH. Primary care physicians and specialist physicians participated in qualitative interviews, usability testing and an implementation survey. The CDS was configured in two formats—a best practice alert (BPA) and an in-basket message and subsequently deployed in the EHR in silent mode. The key themes that emerged from the analysis of interview transcripts included understanding and awareness of FH, clinical workflow, physician preferences and value of CDS tools, perspectives on patient needs and values and dissemination and implementation. Recommendations related to usability included preferred CDS format and placement, content, timing and frequency, and level of alert urgency/prioritization. In response to the survey, 84.6% of physicians agreed that the CDS would improve early FH diagnosis and 92.3% agreed that it would help them identify and manage FH patients. Physician feedback led to iterative CDS refinement. In summary, we developed a CDS tool for FH using an implementation science framework and physician feedback. Initial deployment revealed a significant burden of FH and the potential for the CDS tool to have a large impact.

Because polygenic risk scores (PRSs) for coronary heart disease (CHD) are derived from mainly European ancestry (EA) cohorts, their validity in African ancestry (AA) and Hispanic ethnicity (HE) individuals is unclear. We investigated associations of “restricted” and genome-wide PRSs with CHD in three major racial and ethnic groups in the U.S. The eMERGE cohort (mean age 48 ± 14 years, 58% female) included 45,645 EA, 7,597 AA, and 2,493 HE individuals. We assessed two restricted PRSs (PRS(Tikkanen) and PRS(Tada); 28 and 50 variants, respectively) and two genome-wide PRSs (PRS(metaGRS) and PRS(LDPred); 1.7 M and 6.6 M variants, respectively) derived from EA cohorts. Over a median follow-up of 11.1 years, 2,652 incident CHD events occurred. Hazard and odds ratios for the association of PRSs with CHD were similar in EA and HE cohorts but lower in AA cohorts. Genome-wide PRSs were more strongly associated with CHD than restricted PRSs were. PRS(metaGRS), the best performing PRS, was associated with CHD in all three cohorts; hazard ratios (95% CI) per 1 SD increase were 1.53 (1.46–1.60), 1.53 (1.23–1.90), and 1.27 (1.13–1.43) for incident CHD in EA, HE, and AA individuals, respectively. The hazard ratios were comparable in the EA and HE cohorts (p(interaction) = 0.77) but were significantly attenuated in AA individuals (p(interaction)= 2.9 × 10(−3)). These results highlight the potential clinical utility of PRSs for CHD as well as the need to assemble diverse cohorts to generate ancestry- and ethnicity PRSs.