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Understanding genetic architecture of plasma lipidome could provide better insights into lipid metabolism and its link to cardiovascular diseases (CVDs). Here, we perform genome-wide association analyses of 141 lipid species (n = 2,181 individuals), followed by phenome-wide scans with 25 CVD related phenotypes (n = 511,700 individuals). We identify 35 lipid-species-associated loci (P

Background We asked whether, after excluding familial hypercholesterolemia, individuals with high low-density lipoprotein cholesterol ( LDL -C) or triacylglyceride levels and a family history of the same hyperlipidemia have greater coronary artery disease risk or different lipidomic profiles compared with population-based hyperlipidemias. Methods and Results We determined incident coronary artery disease risk for 755 members of 66 hyperlipidemic families (≥2 first-degree relatives with similar hyperlipidemia) and 19 644 Finnish FINRISK population study participants. We quantified 151 circulating lipid species from 550 members of 73 hyperlipidemic families and 897 FINRISK participants using mass spectrometric shotgun lipidomics. Familial hypercholesterolemia was excluded using functional LDL receptor testing and genotyping. Hyperlipidemias ( LDL -C or triacylglycerides >90th population percentile) associated with increased coronary artery disease risk in meta-analysis of the hyperlipidemic families and the population cohort (high LDL -C: hazard ratio, 1.74 [95% CI, 1.48-2.04]; high triacylglycerides: hazard ratio, 1.38 [95% CI, 1.09-1.74]). Risk estimates were similar in the family and population cohorts also after adjusting for lipid-lowering medication. In lipidomic profiling, high LDL -C associated with 108 lipid species, and high triacylglycerides associated with 131 lipid species in either cohort (at 5% false discovery rate; P-value range 0.038-2.3×10-56). Lipidomic profiles were highly similar for hyperlipidemic individuals in the families and the population ( LDL -C: r=0.80; triacylglycerides: r=0.96; no lipid species deviated between the cohorts). Conclusions Hyperlipidemias with family history conferred similar coronary artery disease risk as population-based hyperlipidemias. We identified distinct lipidomic profiles associated with high LDL -C and triacylglycerides. Lipidomic profiles were similar between hyperlipidemias with family history and population-ascertained hyperlipidemias, providing evidence of similar and overlapping underlying mechanisms.

BACKGROUND: Despite a proposed causal role for LDL-C (low-density lipoprotein cholesterol) in aortic stenosis (AS), randomized controlled trials of lipid-lowering therapy failed to prevent severe AS. We aimed to assess the impact on AS and peak velocity across the aortic valve conferred by lifelong alterations in LDL-C levels mediated by protein-disrupting variants in 3 clinically significant genes for LDL (low-density lipoprotein) metabolism (LDLR , APOB , and PCSK9). METHODS: We used sequencing data and electronic health records from UK Biobank (UKB) and All of Us and magnetic resonance imaging data from UKB. We identified predicted protein-disrupting variants with the Loss Of Function Transcript Effect Estimator (LOFTEE) and AlphaMissense algorithms and evaluated their associations with LDL-C and peak velocity across the aortic valve (UK Biobank), as well as diagnosed AS and aortic valve replacement (UK Biobank and All of Us). RESULTS: We included 421 049 unrelated participants (5621 with AS) in UKB and 195 519 unrelated participants (1087 with AS) in All of Us. Carriers of protein-disrupting variants in LDLR had higher mean LDL-C (UKB: +42.6 mg/dL; P =4.4e-237) and greater risk of AS (meta-analysis: odds ratio, 3.52 [95% CI, 2.39–5.20]; P =2.3e-10) and aortic valve replacement (meta-analysis: odds ratio, 3.78 [95% CI, 2.26–6.32]; P =4.0e-7). Carriers of protein-disrupting variants in APOB or PCSK9 had lower mean LDL-C (UKB: –32.3 mg/dL; P <5e-324) and lower risk of AS (meta-analysis: odds ratio, 0.49 [95% CI, 0.31–0.75]; P =0.001) and aortic valve replacement (meta-analysis: odds ratio, 0.54 [95% CI, 0.30–0.97]; P =0.04). Among 57 371 UKB imaging substudy participants, peak velocities across the aortic valve were greater in carriers of protein-disrupting variants in LDLR (+12.2 cm/s; P =1.6e-5) and lower in carriers of protein-disrupting variants in PCSK9 (–6.9 cm/s; P =0.022). CONCLUSIONS: Rare genetic variants that confer lifelong higher or lower LDL-C levels are associated with substantially increased and decreased risk of AS, respectively. Early and sustained lipid-lowering therapy may slow or prevent AS development. [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF) is a globally prevalent cardiac arrhythmia with significant genetic underpinnings, as highlighted by recent large-scale genetic studies. A prominent clinical and genetic overlap exists between AF, heritable ventricular cardiomyopathies, and arrhythmia syndromes, underlining the potential of AF as an early indicator of severe ventricular disease in younger individuals. Indeed, several recent studies have demonstrated meaningful yields of rare pathogenic variants among early-onset AF patients (∼4%–11%), most notably for cardiomyopathy genes in which rare variants are considered clinically actionable. Genetic testing thus presents a promising opportunity to identify monogenetic defects linked to AF and inherited cardiac conditions, such as cardiomyopathy, and may contribute to prognosis and management in early-onset AF patients. A first step towards recognizing this monogenic contribution was taken with the Class IIb recommendation for genetic testing in AF patients aged 45 years or younger by the 2023 American College of Cardiology/American Heart Association guidelines for AF. By identifying pathogenic genetic variants known to underlie inherited cardiomyopathies and arrhythmia syndromes, a personalized care pathway can be developed, encompassing more tailored screening, cascade testing, and potentially genotype-informed prognosis and preventive measures. However, this can only be ensured by frameworks that are developed and supported by all stakeholders. Ambiguity in test results such as variants of uncertain significance remain a major challenge and as many as ∼60% of people with early-onset AF might carry such variants. Patient education (including pretest counselling), training of genetic teams, selection of high-confidence genes, and careful reporting are strategies to mitigate this. Further challenges to implementation include financial barriers, insurability issues, workforce limitations, and the need for standardized definitions in a fast-moving field. Moreover, the prevailing genetic evidence largely rests on European descent populations, underscoring the need for diverse research cohorts and international collaboration. Embracing these challenges and the potential of genetic testing may improve AF care. However, further research—mechanistic, translational, and clinical—is urgently needed. [ABSTRACT FROM AUTHOR]

Familial combined hyperlipidemia (FCH) is a complex and common familial dyslipidemia characterized by elevated total cholesterol and/or triglyceride levels with over five-fold risk of coronary heart disease. The genetic architecture and contribution of rare Mendelian and common variants to FCH susceptibility is unknown. In 53 Finnish FCH families, we genotyped and imputed nine million variants in 715 family members with DNA available. We studied the enrichment of variants previously implicated with monogenic dyslipidemias and/or lipid levels in the general population by comparing allele frequencies between the FCH families and population samples. We also constructed weighted polygenic scores using 212 lipid-associated SNPs and estimated the relative contributions of Mendelian variants and polygenic scores to the risk of FCH in the families. We identified, across the whole allele frequency spectrum, an enrichment of variants known to elevate, and a deficiency of variants known to lower LDL-C and/or TG levels among both probands and affected FCH individuals. The score based on TG associated SNPs was particularly high among affected individuals compared to non-affected family members. Out of 234 affected FCH individuals across the families, seven (3%) carried Mendelian variants and 83 (35%) showed high accumulation of either known LDL-C or TG elevating variants by having either polygenic score over the 90th percentile in the population. The positive predictive value of high score was much higher for affected FCH individuals than for similar sporadic cases in the population. FCH is highly polygenic, supporting the hypothesis that variants across the whole allele frequency spectrum contribute to this complex familial trait. Polygenic SNP panels improve identification of individuals affected with FCH, but their clinical utility remains to be defined.

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. In this study, we sought to discover epidemiologic correlates and genetic determinants of aortic distensibility and strain. 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. 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. Genetic determinants of aortic function influence risk for stroke and coronary artery disease and may lead to novel targets for medical intervention. [Display omitted] [ABSTRACT FROM AUTHOR]

Beyond serving as a marker for insufficient physical activity, sedentary behavior may directly affect future cardiovascular (CV) disease risk. This study sought to examine associations between accelerometer-measured sedentary behavior with risk of specific CV outcomes, including potential relations with moderate to vigorous physical activity (MVPA). Among participants of the UK Biobank prospective cohort study, we fit Cox models adjusted for demographic and lifestyle factors to assess associations between accelerometer-measured daily sedentary time with incident atrial fibrillation (AF), myocardial infarction (MI), heart failure (HF), and CV mortality. We assessed the potential effect of MVPA on associations between sedentary time and CV disease by including MVPA as an adjustment variable, as well as performing subgroup analyses stratified at the guideline-recommended MVPA threshold (ie, ≥150 min/wk). We then performed compositional analyses to estimate the effects of reallocating sedentary time to other activities. Among 89,530 individuals (age 62 ± 8 years, 56.4% women) undergoing 1 week of accelerometry, median sedentary time was 9.4 h/d (Q1-Q3: 8.2-10.6). In multivariable models, using the second quartile (8.2-9.4 h/d) as a referent, sedentary time in the top quartile (>10.6 h/d) was associated with greater risks of HF (HR: 1.45; 95% CI: 1.28-1.65) and CV mortality (HR: 1.62; 95% CI: 1.34-1.96), with an inflection of risk at 10.6 h/d. Higher sedentary time was also associated with greater risks of incident AF (HR: 1.11; 95% CI: 1.01-1.21) and MI (HR: 1.15; 95% CI: 1.00-1.32), with an approximately linear relation. Associations with HF and CV mortality persisted among individuals meeting guideline-recommended MVPA levels. Among individuals with >10.6 h/d of sedentary time, reallocating sedentary behavior to other activities substantially reduced the excess CV risk conferred by sedentary behavior (eg, 30-minute decrease in sedentary time for HF: HR: 0.93; 95% CI: 0.90-0.96), even among individuals meeting guideline-recommended MVPA (HR: 0.93; 95% CI: 0.87-0.99). Sedentary behavior is broadly associated with future adverse CV outcomes, with particularly prominent effects on HF and CV mortality, where risk inflected at approximately 10.6 h/d. Although guideline-adherent MVPA partially mitigates excess risk, optimizing sedentary behavior appears to be important even among physically active individuals. [Display omitted] [ABSTRACT FROM AUTHOR]

Purpose: To investigate the effects of faricimab, a bispecific antibody targeting VEGF and Ang-2 (thus increasing Tie-2 activity), in patients with CSC based on a recent genetic study that implicated Tie-2 signaling in CSC pathophysiology., Design: A retrospective interventional multicenter case series., Methods: We included patients with chronic CSC (persistent or recurrent SRF for ≥6 months) who received at least one faricimab 6 mg injection between January 1 2022, and April 1 2024,. Study sites included Massachusetts Eye and Ear and University of California San Francisco. Patients with evidence of a choroidal neovascular membrane on color photos, optical coherence tomography (OCT) and/or fluorescein angiography were excluded. 16 eyes (15 patients) met the inclusion criteria. The median central macular thickness at each visit from 52 weeks before to 52 weeks after the first faricimab injection was calculated using automated Heidelberg Spectralis ETDRS subfield measurements., Results: Prior to treatment with faricimab, CSC had been diagnosed a median of 4.1 years (range 0.9-8) earlier and SRF (and intraretinal fluid [IRF] in a subset) had been continuously present for a median of 30 weeks (range 9-257). Decreases in macular thickness were observed in 14/16 eyes after the first faricimab injection and in 14/16 eyes in the full follow-up period compared with prior, 10 of which experienced complete resolution of SRF following the start of the first series of injections at a median of 4 weeks (range 2-25). One eye worsened after the second injection. The median improvement in macular thickness was 40 μm [range -3 to 89.5] (P = .0007). Upon review of OCT images, reductions in macular thickness were consistent with reductions in SRF and/or IRF. Visual acuity improved by 2 lines or more in 6/16 eyes., Conclusions: In a retrospective case series of patients with chronic CSC and longstanding SRF, we observed improvement in macular thickness after intravitreal faricimab. While the small number of patients and variable natural history of CSC preclude definitive conclusions, a randomized controlled trial seems warranted., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: AF risk estimation is feasible using clinical factors, inherited predisposition, and artificial intelligence (AI)-enabled electrocardiogram (ECG) analysis., Objective: To test whether integrating these distinct risk signals improves AF risk estimation., Methods: In the UK Biobank prospective cohort study, we estimated AF risk using three models derived from external populations: the well-validated Cohorts for Aging in Heart and Aging Research in Genomic Epidemiology AF (CHARGE-AF) clinical score, a 1,113,667-variant AF polygenic risk score (PRS), and a published AI-enabled ECG-based AF risk model (ECG-AI). We estimated discrimination of 5-year incident AF using time-dependent area under the receiver operating characteristic (AUROC) and average precision (AP)., Results: Among 49,293 individuals (mean age 65±8 years, 52% women), 825 (2.4%) developed AF within 5 years. Using single models, discrimination of 5-year incident AF was higher using ECG-AI (AUROC 0.705 [95%CI 0.686-0.724]; AP 0.085 [0.071-0.11]) and CHARGE-AF (AUROC 0.785 [0.769-0.801]; AP 0.053 [0.048-0.061]) versus the PRS (AUROC 0.618, [0.598-0.639]; AP 0.038 [0.028-0.045]). The inclusion of all components ("Predict-AF3") was the best performing model (AUROC 0.817 [0.802-0.832]; AP 0.11 [0.091-0.15], p<0.01 vs CHARGE-AF+ECG-AI), followed by the two component model of CHARGE-AF+ECG-AI (AUROC 0.802 [0.786-0.818]; AP 0.098 [0.081-0.13]). Using Predict-AF3, individuals at high AF risk (i.e., 5-year predicted AF risk >2.5%) had a 5-year cumulative incidence of AF of 5.83% (5.33-6.32). At the same threshold, the 5-year cumulative incidence of AF was progressively higher according to the number of models predicting high risk (zero: 0.67% [0.51-0.84], one: 1.48% [1.28-1.69], two: 4.48% [3.99-4.98]; three: 11.06% [9.48-12.61]), and Predict-AF3 achieved favorable net reclassification improvement compared to both CHARGE-AF+ECG-AI (0.039 [0.015-0.066]) and CHARGE-AF+PRS (0.033 [0.0082-0.059])., Conclusions: Integration of clinical, genetic, and AI-derived risk signals improves discrimination of 5-year AF risk over individual components. Models such as Predict-AF3 have substantial potential to improve prioritization of individuals for AF screening and preventive interventions.

Background: Substantial data support a heritable basis for supraventricular tachycardias, but the genetic determinants and molecular mechanisms of these arrhythmias are poorly understood. We sought to identify genetic loci associated with atrioventricular nodal reentrant tachycardia (AVNRT) and atrioventricular accessory pathways or atrioventricular reciprocating tachycardia (AVAPs/AVRT)., Methods: We performed multiancestry meta-analyses of genome-wide association studies to identify genetic loci for AVNRT (4 studies) and AVAP/AVRT (7 studies). We assessed evidence supporting the potential causal effects of candidate genes by analyzing relations between associated variants and cardiac gene expression, performing transcriptome-wide analyses, and examining prior genome-wide association studies., Results: Analyses comprised 2384 AVNRT cases and 106 489 referents, and 2811 AVAP/AVRT cases and 1,483 093 referents. We identified 2 significant loci for AVNRT, which implicate NKX2-5 and TTN as disease susceptibility genes. A transcriptome-wide association analysis supported an association between reduced predicted cardiac expression of NKX2-5 and AVNRT. We identified 3 significant loci for AVAP/AVRT, which implicate SCN5A , SCN10A , and TTN/CCDC141 . Variant associations at several loci have been previously reported for cardiac phenotypes, including atrial fibrillation, stroke, Brugada syndrome, and electrocardiographic intervals., Conclusions: Our findings highlight gene regions associated with ion channel function (AVAP/AVRT), as well as cardiac development and the sarcomere (AVAP/AVRT and AVNRT) as important potential effectors of supraventricular tachycardia susceptibility., Competing Interests: Disclosures Dr Lubitz is a full-time employee of Novartis as of July 2022. Previously, Dr Lubitz received research support from Bristol Myers Squibb/Pfizer, Bayer AG, Boehringer Ingelheim, Fitbit, IBM, Medtronic, and Premier, Inc, and consulted for Bristol Myers Squibb/Pfizer, Bayer AG, Blackstone Life Sciences, and Invitae. Dr Ellinor receives research support from Bayer AG, IBM, and Bristol Myers Squibb/Pfizer and has consulted for Novartis, MyoKardia, and Bayer AG. Dr Damrauer receives research support for RenalytixAI and has consulted for Calico Labs. Dr Svendsen is a member of Medtronic advisory boards and has received speaker honoraria and research grants from Medtronic outside this work. Dr Cutler has consulted for Janssen Scientific. Dr Roselli is supported by a grant from Bayer AG to the Broad Institute focused on the development of therapeutics for cardiovascular disease. The other authors report no conflicts.

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=8.0×10 -4 ) in 708 UK Biobank participants and, surprisingly, with varicose veins (OR=1.31, P=2.3×10 -11 ) and glaucoma (OR=0.82, P=6.9×10 -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., Competing Interests: Declaration of Competing Interests Dr. Rossin and Dr. Rämö are named inventors on a provisional patent application that describes the secondary use of intravitreal Anti-Ang2 medications for use in the treatment of central serous chorioretinopathy. Dr. Ellinor receives sponsored research support from Bayer AG, IBM Research, Bristol Myers Squibb, Pfizer and Novo Nordisk; he has also served on advisory boards or consulted for MyoKardia and Bayer AG. The remaining authors declare no competing interests.

Purpose: Apolipoprotein E4 (APOE4), a known risk factor for Alzheimer's disease, has controversially been associated with reduced risk of primary open-angle glaucoma (POAG) and age-related macular degeneration (AMD). Here, we sought to systematically quantify the associations of APOE haplotypes with age-related ocular diseases and to assess their scope and age-dependency., Methods: We included genetic and registry data from 412,171 Finnish individuals in the FinnGen study. Disease endpoints were defined using nationwide registries. APOE genotypes were directly genotyped using Illumina and Affymetrix arrays or imputed using a custom Finnish reference panel. We evaluated the disease associations of APOE genotypes containing ε2 (without ε4) and ε4 (without ε2) compared with the ε3ε3 genotype using logistic regressions stratified by age., Results: APOE ε4 enriched haplotypes were inversely associated with overall glaucoma (odds ratio [OR] = 0.95, 95% confidence interval [CI] = 0.92-0.99, P = 0.0047), and its subtypes POAG (OR = 0.95, P = 0.027), normal-tension glaucoma (OR = 0.87, P = 0.0058), and suspected glaucoma (OR = 0.95, P = 0.014). Individuals with the ε4 allele also had lower odds for AMD (OR = 0.80, 95% CI = 0.76-0.84, P < 0.001), seen both in dry and neovascular subgroups. A slight negative association was also detected in senile cataract, but this was not reproducible in age-group analyses., Conclusions: Our results support prior evidence of the inverse association of APOE ε4 with glaucoma, but the association was weaker than for AMD. We could not show an association with exfoliation glaucoma, supporting the hypothesis that APOE may be involved in regulating retinal ganglion cell degeneration rather than intraocular pressure.

Background: While previous studies have reported associations of pericardial adipose tissue (PAT) with cardiovascular diseases such as atrial fibrillation and coronary artery disease, they have been limited in sample size or drawn from selected populations. Additionally, the genetic determinants of PAT remain largely unknown. We aimed to evaluate the association of PAT with prevalent and incident cardiovascular disease and to elucidate the genetic basis of PAT in a large population cohort., Methods: A deep learning model was trained to quantify PAT area from four-chamber magnetic resonance images in the UK Biobank using semantic segmentation. Cross-sectional and prospective cardiovascular disease associations were evaluated, controlling for sex and age. A genome-wide association study was performed, and a polygenic score (PGS) for PAT was examined in 453,733 independent FinnGen study participants., Results: A total of 44,725 UK Biobank participants (51.7% female, mean [SD] age 64.1 [7.7] years) were included. PAT was positively associated with male sex (β = +0.76 SD in PAT), age ( r = 0.15), body mass index (BMI; r = 0.47) and waist-to-hip ratio ( r = 0.55) (P < 1×10 -230 ). PAT was more elevated in prevalent heart failure (β = +0.46 SD units) and type 2 diabetes (β = +0.56) than in coronary artery disease (β = +0.22) or AF (β = +0.18). PAT was associated with incident heart failure (HR = 1.29 per +1 SD in PAT [95% CI 1.17-1.43]) and type 2 diabetes (HR = 1.63 [1.51-1.76]) during a mean 3.2 (±1.5) years of follow-up; the associations remained significant when controlling for BMI. We identified 5 novel genetic loci for PAT and implicated transcriptional regulators of adipocyte morphology and brown adipogenesis ( EBF1 , EBF2 and CEBPA ) and regulators of visceral adiposity ( WARS2 and TRIB2 ). The PAT PGS was associated with T2D, heart failure, coronary artery disease and atrial fibrillation in FinnGen (ORs 1.03-1.06 per +1 SD in PGS, P < 2×10 -10 )., Conclusions: PAT shares genetic determinants with abdominal adiposity and is an independent predictor of incident type 2 diabetes and heart failure.

Valvular heart disease is associated with a high global burden of disease. Even mild aortic stenosis confers increased morbidity and mortality, prompting interest in understanding normal variation in valvular function at scale. We developed a deep learning model to study velocity-encoded magnetic resonance imaging in 47,223 UK Biobank participants. We calculated eight traits, including peak velocity, mean gradient, aortic valve area, forward stroke volume, mitral and aortic regurgitant volume, greatest average velocity, and ascending aortic diameter. We then computed sex-stratified reference ranges for these phenotypes in up to 31,909 healthy individuals. In healthy individuals, we found an annual decrement of 0.03cm 2 in the aortic valve area. Participants with mitral valve prolapse had a 1 standard deviation [SD] higher mitral regurgitant volume (P=9.6 × 10 -12 ), and those with aortic stenosis had a 4.5 SD-higher mean gradient (P=1.5 × 10 -431 ), validating the derived phenotypes' associations with clinical disease. Greater levels of ApoB, triglycerides, and Lp(a) assayed nearly 10 years prior to imaging were associated with higher gradients across the aortic valve. Metabolomic profiles revealed that increased glycoprotein acetyls were also associated with an increased aortic valve mean gradient (0.92 SD, P=2.1 x 10 -22 ). Finally, velocity-derived phenotypes were risk markers for aortic and mitral valve surgery even at thresholds below what is considered relevant disease currently. Using machine learning to quantify the rich phenotypic data of the UK Biobank, we report the largest assessment of valvular function and cardiovascular disease in the general population.

Background: Hyperlipidemia is a highly heritable risk factor for coronary artery disease (CAD). While monogenic familial hypercholesterolemia associates with severely increased CAD risk, it remains less clear to what extent a high polygenic load of a large number of LDL (low-density lipoprotein) cholesterol (LDL-C) or triglyceride (TG)-increasing variants associates with increased CAD risk., Methods: We derived polygenic risk scores (PRSs) with ≈6M variants separately for LDL-C and TG with weights from a UK Biobank-based genome-wide association study with ≈324K samples. We evaluated the impact of polygenic hypercholesterolemia and hypertriglyceridemia to lipid levels in 27 039 individuals from the National FINRISK Study (FINRISK) cohort and to CAD risk in 135 638 individuals (13 753 CAD cases) from the FinnGen project (FinnGen)., Results: In FINRISK, median LDL-C was 3.39 (95% CI, 3.38-3.40) mmol/L, and it ranged from 2.87 (95% CI, 2.82-2.94) to 3.78 (95% CI, 3.71-3.83) mmol/L between the lowest and highest 5% of the LDL-C PRS distribution. Median TG was 1.19 (95% CI, 1.18-1.20) mmol/L, ranging from 0.97 (95% CI, 0.94-1.00) to 1.55 (95% CI, 1.48-1.61) mmol/L with the TG PRS. In FinnGen, comparing the highest 5% of the PRS to the lowest 95%, CAD odds ratio was 1.36 (95% CI, 1.24-1.49) for the LDL-C PRS and 1.31 (95% CI, 1.19-1.43) for the TG PRS. These estimates were only slightly attenuated when adjusting for a CAD PRS (odds ratio, 1.26 [95% CI, 1.16-1.38] for LDL-C and 1.24 [95% CI, 1.13-1.36] for TG PRS)., Conclusions: The CAD risk associated with a high polygenic load for lipid-increasing variants was proportional to their impact on lipid levels and partially overlapping with a CAD PRS. In contrast with a PRS for CAD, the lipid PRSs point to known and directly modifiable risk factors providing additional guidance for clinical translation.