Rare genetic variation in VE-PTP is associated with central serous chorioretinopathy, venous dysfunction and glaucoma.

Central serous chorioretinopathy (CSC) is a fluid maculopathy whose etiology is not well understood. Abnormal choroidal veins in CSC patients have been shown to have similarities with varicose veins. To identify potential mechanisms, we analyzed genotype data from 1,477 CSC patients and 455,449 controls in FinnGen. We identified an association for a low-frequency (AF=0.5%) missense variant (rs113791087) in the gene encoding vascular endothelial protein tyrosine phosphatase (VE-PTP) (OR=2.85, P=4.5×10 -9 ). This was confirmed in a meta-analysis of 2,452 CSC patients and 865,767 controls from 4 studies (OR=3.06, P=7.4×10 -15 ). Rs113791087 was associated with a 56% higher prevalence of retinal abnormalities (35.3% vs 22.6%, P=8.0x10 -4 ) in 708 UK Biobank participants and, surprisingly, with varicose veins (OR=1.31, P=2.3x10 -11 ) and glaucoma (OR=0.82, P=6.9x10 -9 ). Predicted loss-of-function variants in VEPTP, though rare in number, were associated with CSC in All of Us (OR=17.10, P=0.018). These findings highlight the significance of VE-PTP in diverse ocular and systemic vascular diseases.

Deep learning of left atrial structure and function provides link to atrial fibrillation risk.

Increased left atrial volume and decreased left atrial function have long been associated with atrial fibrillation. The availability of large-scale cardiac magnetic resonance imaging data paired with genetic data provides a unique opportunity to assess the genetic contributions to left atrial structure and function, and understand their relationship with risk for atrial fibrillation. Here, we use deep learning and surface reconstruction models to measure left atrial minimum volume, maximum volume, stroke volume, and emptying fraction in 40,558 UK Biobank participants. In a genome-wide association study of 35,049 participants without pre-existing cardiovascular disease, we identify 20 common genetic loci associated with left atrial structure and function. We find that polygenic contributions to increased left atrial volume are associated with atrial fibrillation and its downstream consequences, including stroke. Through Mendelian randomization, we find evidence supporting a causal role for left atrial enlargement and dysfunction on atrial fibrillation risk.

TAD boundary deletion causes PITX2-related cardiac electrical and structural defects.

While 3D chromatin organization in topologically associating domains (TADs) and loops mediating regulatory element-promoter interactions is crucial for tissue-specific gene regulation, the extent of their involvement in human Mendelian disease is largely unknown. Here, we identify 7 families presenting a new cardiac entity associated with a heterozygous deletion of 2 CTCF binding sites on 4q25, inducing TAD fusion and chromatin conformation remodeling. The CTCF binding sites are located in a gene desert at 1 Mb from the Paired-like homeodomain transcription factor 2 gene (PITX2). By introducing the ortholog of the human deletion in the mouse genome, we recapitulate the patient phenotype and characterize an opposite dysregulation of PITX2 expression in the sinoatrial node (ectopic activation) and ventricle (reduction), respectively. Chromatin conformation assay performed in human induced pluripotent stem cell-derived cardiomyocytes harboring the minimal deletion identified in family#1 reveals a conformation remodeling and fusion of TADs. We conclude that TAD remodeling mediated by deletion of CTCF binding sites causes a new autosomal dominant Mendelian cardiac disorder.

Key variants via the Alzheimer's Disease Sequencing Project whole genome sequence data.

INTRODUCTION: Genome-wide association studies (GWAS) have identified loci associated with Alzheimer's disease (AD) but did not identify specific causal genes or variants within those loci. Analysis of whole genome sequence (WGS) data, which interrogates the entire genome and captures rare variations, may identify causal variants within GWAS loci. METHODS: We performed single common variant association analysis and rare variant aggregate analyses in the pooled population (N cases = 2184, N controls = 2383) and targeted analyses in subpopulations using WGS data from the Alzheimer's Disease Sequencing Project (ADSP). The analyses were restricted to variants within 100 kb of 83 previously identified GWAS lead variants. RESULTS: Seventeen variants were significantly associated with AD within five genomic regions implicating the genes OARD1/NFYA/TREML1, JAZF1, FERMT2, and SLC24A4. KAT8 was implicated by both single variant and rare variant aggregate analyses. DISCUSSION: This study demonstrates the utility of leveraging WGS to gain insights into AD loci identified via GWAS.

Thrombosis Risk in Double Heterozygous Carriers of Factor V Leiden and Prothrombin G20210A in FinnGen and the UK Biobank.

The Factor V Leiden (FVL, rs6025) and prothrombin G20210A (PTGM, rs1799963) polymorphisms are two of the most well-studied genetic risk factors for venous thromboembolism (VTE). However, double heterozygosity (DH) for FVL and PTGM remains poorly understood, with prior studies in marked disagreement about the thrombosis risk conferred by the DH genotype. Utilizing multi-dimensional data from the UK Biobank (UKB) and the FinnGen biorepositories, we evaluated the clinical impact of DH carrier status across 937,939 individuals. We found that 662 participants (0.07%) were DH carriers. After adjustment for age, sex, and ancestry, DH individuals experienced a markedly elevated risk of VTE compared to wild-type individuals (OR=5.24, 95% CI: 4.01 - 6.84; P=4.8 x 10-34), which approximated the risk conferred by FVL homozygosity. A secondary analysis restricted to UKB participants (N=445,144) found that effect size estimates for the DH genotype remained largely unchanged (OR=4.53, 95% CI: 3.42 - 5.90; P<1 x 10-16) after adjustment for commonly cited VTE risk factors such as body mass index, blood type, and markers of inflammation. By contrast, the DH genotype was not associated with a significantly higher risk of any arterial thrombosis phenotype, including stroke, myocardial infarction, and peripheral artery disease. In summary, we leveraged population-scale genomic datasets to conduct the largest study to date of the DH genotype and were able to establish far more precise effect size estimates than previously possible. Our findings indicate that the DH genotype may occur as frequently as FVL homozygosity and confers a similarly increased risk of VTE.

Lipid levels and risk of acute pancreatitis using bidirectional Mendelian randomization.

Previous studies found lipid levels, especially triglycerides (TG), are associated with acute pancreatitis, but their causalities and bi-directions were not fully examined. We determined whether abnormal levels of TG, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) are precursors and/or consequences of acute pancreatitis using bidirectional two-sample Mendelian randomization (MR) with two non-overlapping genome-wide association study (GWAS) summary statistics for lipid levels and acute pancreatitis. We found phenotypic associations that both higher TG levels and lower HDL-C levels contributed to increased risk of acute pancreatitis. Our GWAS meta-analysis of acute pancreatitis identified seven independent signals. Genetically predicted TG was positively associated with acute pancreatitis when using the variants specifically associated with TG using univariable MR [Odds ratio (OR), 95% CI 2.02, 1.22-3.31], but the reversed direction from acute pancreatitis to TG was not observed (mean difference = 0.003, SE = 0.002, P-value = 0.138). However, a bidirectional relationship of HDL-C and acute pancreatitis was observed: A 1-SD increment of genetically predicted HDL-C was associated with lower risk of acute pancreatitis (OR, 95% CI 0.84, 0.76-0.92) and genetically predisposed individuals with acute pancreatitis have, on average, 0.005 SD lower HDL-C (mean difference = - 0.005, SE = 0.002, P-value = 0.004). Our MR analysis confirms the evidence of TG as a risk factor of acute pancreatitis but not a consequence. A potential bidirectional relationship of HDL-C and acute pancreatitis occurs and raises the prospect of HDL-C modulation in the acute pancreatitis prevention and treatment.

Key variants via Alzheimer's Disease Sequencing Project whole genome sequence data.

INTRODUCTION: Genome-wide association studies (GWAS) have identified loci associated with Alzheimer's disease (AD) but did not identify specific causal genes or variants within those loci. Analysis of whole genome sequence (WGS) data, which interrogates the entire genome and captures rare variations, may identify causal variants within GWAS loci. METHODS: We performed single common variant association analysis and rare variant aggregate analyses in the pooled population (N cases=2,184, N controls=2,383) and targeted analyses in sub-populations using WGS data from the Alzheimer's Disease Sequencing Project (ADSP). The analyses were restricted to variants within 100 kb of 83 previously identified GWAS lead variants. RESULTS: Seventeen variants were significantly associated with AD within five genomic regions implicating the genes OARD1/NFYA/TREML1, JAZF1, FERMT2, and SLC24A4. KAT8 was implicated by both single variant and rare variant aggregate analyses. DISCUSSION: This study demonstrates the utility of leveraging WGS to gain insights into AD loci identified via GWAS.

Association of Common and Rare Variants with Alzheimer's Disease in over 13,000 Diverse Individuals with Whole-Genome Sequencing from the Alzheimer's Disease Sequencing Project.

Alzheimer's Disease (AD) is a common disorder of the elderly that is both highly heritable and genetically heterogeneous. Here, we investigated the association between AD and both common variants and aggregates of rare coding and noncoding variants in 13,371 individuals of diverse ancestry with whole genome sequence (WGS) data. Pooled-population analyses identified genetic variants in or near APOE, BIN1, and LINC00320 significantly associated with AD (p < 5×10-8). Population-specific analyses identified a haplotype on chromosome 14 including PSEN1 associated with AD in Hispanics, further supported by aggregate testing of rare coding and noncoding variants in this region. Finally, we observed suggestive associations (p < 5×10-5) of aggregates of rare coding rare variants in ABCA7 among non-Hispanic Whites (p=5.4×10-6), and rare noncoding variants in the promoter of TOMM40 distinct of APOE in pooled-population analyses (p=7.2×10-8). Complementary pooled-population and population-specific analyses offered unique insights into the genetic architecture of AD.

Genetic Susceptibility to Atrial Fibrillation Identified via Deep Learning of 12-Lead Electrocardiograms.

BACKGROUND: Artificial intelligence (AI) models applied to 12-lead ECG waveforms can predict atrial fibrillation (AF), a heritable and morbid arrhythmia. However, the factors forming the basis of risk predictions from AI models are usually not well understood. We hypothesized that there might be a genetic basis for an AI algorithm for predicting the 5-year risk of new-onset AF using 12-lead ECGs (ECG-AI)-based risk estimates. METHODS: We applied a validated ECG-AI model for predicting incident AF to ECGs from 39 986 UK Biobank participants without AF. We then performed a genome-wide association study (GWAS) of the predicted AF risk and compared it with an AF GWAS and a GWAS of risk estimates from a clinical variable model. RESULTS: In the ECG-AI GWAS, we identified 3 signals (P<5×10-8) at established AF susceptibility loci marked by the sarcomeric gene TTN and sodium channel genes SCN5A and SCN10A. We also identified 2 novel loci near the genes VGLL2 and EXT1. In contrast, the clinical variable model prediction GWAS indicated a different genetic profile. In genetic correlation analysis, the prediction from the ECG-AI model was estimated to have a higher correlation with AF than that from the clinical variable model. CONCLUSIONS: Predicted AF risk from an ECG-AI model is influenced by genetic variation implicating sarcomeric, ion channel and body height pathways. ECG-AI models may identify individuals at risk for disease via specific biological pathways.

Genetic Burden of TNNI3K in Diagnostic Testing of Patients With Dilated Cardiomyopathy and Supraventricular Arrhythmias.

BACKGROUND: Genetic variants in TNNI3K (troponin-I interacting kinase) have previously been associated with dilated cardiomyopathy (DCM), cardiac conduction disease, and supraventricular tachycardias. However, the link between TNNI3K variants and these cardiac phenotypes shows a lack of consensus concerning phenotype and protein function. METHODS: We describe a systematic retrospective study of a cohort of patients undergoing genetic testing for cardiac arrhythmias and cardiomyopathy including TNNI3K. We further performed burden testing of TNNI3K in the UK Biobank. For 2 novel TNNI3K variants, we tested cosegregation. TNNI3K kinase function was estimated by TNNI3K autophosphorylation assays. RESULTS: We demonstrate enrichment of rare coding TNNI3K variants in DCM patients in the Amsterdam cohort. In the UK Biobank, we observed an association between TNNI3K missense (but not loss-of-function) variants and DCM and atrial fibrillation. Furthermore, we demonstrate genetic segregation for 2 rare variants, TNNI3K-p.Ile512Thr and TNNI3K-p.His592Tyr, with phenotypes consisting of DCM, cardiac conduction disease, and supraventricular tachycardia, together with increased autophosphorylation. In contrast, TNNI3K-p.Arg556_Asn590del, a likely benign variant, demonstrated depleted autophosphorylation. CONCLUSIONS: Our findings demonstrate an increased burden of rare coding TNNI3K variants in cardiac patients with DCM. Furthermore, we present 2 novel likely pathogenic TNNI3K variants with increased autophosphorylation, suggesting that enhanced autophosphorylation is likely to drive pathogenicity.

Overlap of Genetic Loci for Central Serous Chorioretinopathy With Age-Related Macular Degeneration.

Importance: Central serous chorioretinopathy (CSC) is a serous maculopathy of unknown etiology. Two of 3 previously reported CSC genetic risk loci are also associated with AMD. Improved understanding of CSC genetics may broaden our understanding of this genetic overlap and unveil mechanisms in both diseases. Objective: To identify novel genetic risk factors for CSC and compare genetic risk factors for CSC and AMD. Design, Setting, and Participants: Using International Classification of Diseases, Ninth (ICD-9) and Tenth (ICD-10) Revision code-based inclusion and exclusion criteria, patients with CSC and controls were identified in both the FinnGen study and the Estonian Biobank (EstBB). Also included in a meta-analysis were previously reported patients with chronic CSC and controls. Data were analyzed from March 1 to September 31, 2022. Main Outcomes and Measures: Genome-wide association studies (GWASs) were performed in the biobank-based cohorts followed by a meta-analysis of all cohorts. The expression of genes prioritized by the polygenic priority score and nearest-gene methods were assessed in cultured choroidal endothelial cells and public ocular single-cell RNA sequencing data sets. The predictive utility of polygenic scores (PGSs) for CSC and AMD were evaluated in the FinnGen study. Results: A total of 1176 patients with CSC and 526 787 controls (312 162 female [59.3%]) were included in this analysis: 552 patients with CSC and 343 461 controls were identified in the FinnGen study, 103 patients with CSC and 178 573 controls were identified in the EstBB, and 521 patients with chronic CSC and 3577 controls were included in a meta-analysis. Two previously reported CSC risk loci were replicated (near CFH and GATA5) and 3 novel loci were identified (near CD34/46, NOTCH4, and PREX1). The CFH and NOTCH4 loci were associated with AMD but in the opposite direction. Prioritized genes showed increased expression in cultured choroidal endothelial cells compared with other genes in the loci (median [IQR] of log 2 [counts per million], 7.3 [0.6] vs 4.7 [3.7]; P = .004) and were differentially expressed in choroidal vascular endothelial cells in single-cell RNA sequencing data (mean [SD] fold change, 2.05 [0.38] compared with other cell types; P < 7.1 × 10-20). A PGS for AMD was predictive of reduced CSC risk (odds ratio, 0.76; 95% CI, 0.70-0.83 per +1 SD in AMD-PGS; P = 7.4 × 10-10). This association may have been mediated by loci containing complement genes. Conclusions and Relevance: In this 3-cohort genetic association study, 5 genetic risk loci for CSC were identified, highlighting a likely role for genes involved in choroidal vascular function and complement regulation. Results suggest that polygenic AMD risk was associated with reduced risk of CSC and that this genetic overlap was largely due to loci containing complement genes.

Genetics of myocardial interstitial fibrosis in the human heart and association with disease.

Myocardial interstitial fibrosis is associated with cardiovascular disease and adverse prognosis. Here, to investigate the biological pathways that underlie fibrosis in the human heart, we developed a machine learning model to measure native myocardial T1 time, a marker of myocardial fibrosis, in 41,505 UK Biobank participants who underwent cardiac magnetic resonance imaging. Greater T1 time was associated with diabetes mellitus, renal disease, aortic stenosis, cardiomyopathy, heart failure, atrial fibrillation, conduction disease and rheumatoid arthritis. Genome-wide association analysis identified 11 independent loci associated with T1 time. The identified loci implicated genes involved in glucose transport (SLC2A12), iron homeostasis (HFE, TMPRSS6), tissue repair (ADAMTSL1, VEGFC), oxidative stress (SOD2), cardiac hypertrophy (MYH7B) and calcium signaling (CAMK2D). Using a transforming growth factor ß1-mediated cardiac fibroblast activation assay, we found that 9 of the 11 loci consisted of genes that exhibited temporal changes in expression or open chromatin conformation supporting their biological relevance to myofibroblast cell state acquisition. By harnessing machine learning to perform large-scale quantification of myocardial interstitial fibrosis using cardiac imaging, we validate associations between cardiac fibrosis and disease, and identify new biologically relevant pathways underlying fibrosis.

The Genetic Determinants of Aortic Distention.

BACKGROUND: As the largest conduit vessel, the aorta is responsible for the conversion of phasic systolic inflow from ventricular ejection into more continuous peripheral blood delivery. Systolic distention and diastolic recoil conserve energy and are enabled by the specialized composition of the aortic extracellular matrix. Aortic distensibility decreases with age and vascular disease. OBJECTIVES: In this study, we sought to discover epidemiologic correlates and genetic determinants of aortic distensibility and strain. METHODS: We trained a deep learning model to quantify thoracic aortic area throughout the cardiac cycle from cardiac magnetic resonance images and calculated aortic distensibility and strain in 42,342 UK Biobank participants. RESULTS: Descending aortic distensibility was inversely associated with future incidence of cardiovascular diseases, such as stroke (HR: 0.59 per SD; P = 0.00031). The heritabilities of aortic distensibility and strain were 22% to 25% and 30% to 33%, respectively. Common variant analyses identified 12 and 26 loci for ascending and 11 and 21 loci for descending aortic distensibility and strain, respectively. Of the newly identified loci, 22 were not significantly associated with thoracic aortic diameter. Nearby genes were involved in elastogenesis and atherosclerosis. Aortic strain and distensibility polygenic scores had modest effect sizes for predicting cardiovascular outcomes (delaying or accelerating disease onset by 2%-18% per SD change in scores) and remained statistically significant predictors after accounting for aortic diameter polygenic scores. CONCLUSIONS: Genetic determinants of aortic function influence risk for stroke and coronary artery disease and may lead to novel targets for medical intervention.

Common and rare variants associated with cardiometabolic traits across 98,622 whole-genome sequences in the All of Us research program.

All of Us is a biorepository aiming to advance biomedical research by providing various types of data in diverse human populations. Here we present a demonstration project validating the program's genomic data in 98,622 participants. We sought to replicate known genetic associations for three diseases (atrial fibrillation [AF], coronary artery disease, type 2 diabetes [T2D]) and two quantitative traits (height and low-density lipoprotein [LDL]) by conducting common and rare variant analyses. We identified one known risk locus for AF, five loci for T2D, 143 loci for height, and nine loci for LDL. In gene-based burden tests for rare loss-of-function variants, we replicated associations between TTN and AF, GIGYF1 and T2D, ADAMTS17, ACAN, NPR2 and height, APOB, LDLR, PCSK9 and LDL. Our results are consistent with previous literature, indicating that the All of Us program is a reliable resource for advancing the understanding of complex diseases in diverse human populations.

Adjusting for common variant polygenic scores improves yield in rare variant association analyses.

With the emergence of large-scale sequencing data, methods for improving power in rare variant association tests are needed. Here we show that adjusting for common variant polygenic scores improves yield in gene-based rare variant association tests across 65 quantitative traits in the UK Biobank (up to 20% increase at α = 2.6 × 10-6), without marked increases in false-positive rates or genomic inflation. Benefits were seen for various models, with the largest improvements seen for efficient sparse mixed-effects models. Our results illustrate how polygenic score adjustment can efficiently improve power in rare variant association discovery.

Clinical and genetic associations of deep learning-derived cardiac magnetic resonance-based left ventricular mass.

Left ventricular mass is a risk marker for cardiovascular events, and may indicate an underlying cardiomyopathy. Cardiac magnetic resonance is the gold-standard for left ventricular mass estimation, but is challenging to obtain at scale. Here, we use deep learning to enable genome-wide association study of cardiac magnetic resonance-derived left ventricular mass indexed to body surface area within 43,230 UK Biobank participants. We identify 12 genome-wide associations (1 known at TTN and 11 novel for left ventricular mass), implicating genes previously associated with cardiac contractility and cardiomyopathy. Cardiac magnetic resonance-derived indexed left ventricular mass is associated with incident dilated and hypertrophic cardiomyopathies, and implantable cardioverter-defibrillator implant. An indexed left ventricular mass polygenic risk score ≥90th percentile is also associated with incident implantable cardioverter-defibrillator implant in separate UK Biobank (hazard ratio 1.22, 95% CI 1.05-1.44) and Mass General Brigham (hazard ratio 1.75, 95% CI 1.12-2.74) samples. Here, we perform a genome-wide association study of cardiac magnetic resonance-derived indexed left ventricular mass to identify 11 novel variants and demonstrate that cardiac magnetic resonance-derived and genetically predicted indexed left ventricular mass are associated with incident cardiomyopathy.

Machine Learning to Understand Genetic and Clinical Factors Associated With the Pulse Waveform Dicrotic Notch.

BACKGROUND: Absence of a dicrotic notch on finger photoplethysmography is an easily ascertainable and inexpensive trait that has been associated with age and prevalent cardiovascular disease. However, the trait exists along a continuum, and little is known about its genetic underpinnings or prognostic value for incident cardiovascular disease. METHODS: In 169 787 participants in the UK Biobank, we identified absent dicrotic notch on photoplethysmography and created a novel continuous trait reflecting notch smoothness using machine learning. Next, we determined the heritability, genetic basis, polygenic risk, and clinical relations for the binary absent notch trait and the newly derived continuous notch smoothness trait. RESULTS: Heritability of the continuous notch smoothness trait was 7.5%, compared with 5.6% for the binary absent notch trait. A genome-wide association study of notch smoothness identified 15 significant loci, implicating genes including NT5C2 (P=1.2×10-26), IGFBP3 (P=4.8×10-18), and PHACTR1 (P=1.4×10-13), compared with 6 loci for the binary absent notch trait. Notch smoothness stratified risk of incident myocardial infarction or coronary artery disease, stroke, heart failure, and aortic stenosis. A polygenic risk score for notch smoothness was associated with incident cardiovascular disease and all-cause death in UK Biobank participants without available photoplethysmography data. CONCLUSIONS: We found that a machine learning derived continuous trait reflecting dicrotic notch smoothness on photoplethysmography was heritable and associated with genes involved in vascular stiffness. Greater notch smoothness was associated with greater risk of incident cardiovascular disease. Raw digital phenotyping may identify individuals at risk for disease via specific genetic pathways.

Endophenotype effect sizes support variant pathogenicity in monogenic disease susceptibility genes.

Accurate and efficient classification of variant pathogenicity is critical for research and clinical care. Using data from three large studies, we demonstrate that population-based associations between rare variants and quantitative endophenotypes for three monogenic diseases (low-density-lipoprotein cholesterol for familial hypercholesterolemia, electrocardiographic QTc interval for long QT syndrome, and glycosylated hemoglobin for maturity-onset diabetes of the young) provide evidence for variant pathogenicity. Effect sizes are associated with pathogenic ClinVar assertions (P < 0.001 for each trait) and discriminate pathogenic from non-pathogenic variants (area under the curve 0.82-0.84 across endophenotypes). An effect size threshold of ≥ 0.5 times the endophenotype standard deviation nominates up to 35% of rare variants of uncertain significance or not in ClinVar in disease susceptibility genes with pathogenic potential. We propose that variant associations with quantitative endophenotypes for monogenic diseases can provide evidence supporting pathogenicity.

Spatially Distinct Genetic Determinants of Aortic Dimensions Influence Risks of Aneurysm and Stenosis.

BACKGROUND: The left ventricular outflow tract (LVOT) and ascending aorta are spatially complex, with distinct pathologies and embryologic origins. Prior work examined the genetics of thoracic aortic diameter in a single plane. OBJECTIVES: We sought to elucidate the genetic basis for the diameter of the LVOT, aortic root, and ascending aorta. METHODS: Using deep learning, we analyzed 2.3 million cardiac magnetic resonance images from 43,317 UK Biobank participants. We computed the diameters of the LVOT, the aortic root, and at 6 locations of ascending aorta. For each diameter, we conducted a genome-wide association study and generated a polygenic score. Finally, we investigated associations between these scores and disease incidence. RESULTS: A total of 79 loci were significantly associated with at least 1 diameter. Of these, 35 were novel, and most were associated with 1 or 2 diameters. A polygenic score of aortic diameter approximately 13 mm from the sinotubular junction most strongly predicted thoracic aortic aneurysm (n = 427,016; mean HR: 1.42 per SD; 95% CI: 1.34-1.50; P = 6.67 × 10-21). A polygenic score predicting a smaller aortic root was predictive of aortic stenosis (n = 426,502; mean HR: 1.08 per SD; 95% CI: 1.03-1.12; P = 5 × 10-6). CONCLUSIONS: We detected distinct genetic loci underpinning the diameters of the LVOT, aortic root, and at several segments of ascending aorta. We spatially defined a region of aorta whose genetics may be most relevant to predicting thoracic aortic aneurysm. We further described a genetic signature that may predispose to aortic stenosis. Understanding genetic contributions to proximal aortic diameter may enable identification of individuals at risk for aortic disease and facilitate prioritization of therapeutic targets.