Genome-wide association studies of cardiovascular disease.

Genome-wide association studies (GWAS) aim to identify common genetic variants that are associated with traits and diseases. Since 2005, more than 5,000 GWAS have been published for almost as many traits. These studies have offered insights into the loci and genes underlying phenotypic traits, have highlighted genetic correlations across traits and diseases, and are beginning to demonstrate clinical utility by identifying individuals at increased risk for common diseases. GWAS have been widely utilized across cardiovascular diseases and associated phenotypic traits, with insights facilitated by multicenter registry studies and large biobank data sets. In this review, we describe how GWAS have informed the genetic architecture of cardiovascular diseases and the insights they have provided into disease pathophysiology, using archetypal conditions for both common and rare diseases. We also describe how biobank data sets can complement disease-specific studies, particularly for rarer cardiovascular diseases, and how findings from GWAS have the potential to impact on clinical care. Finally, we discuss the outstanding challenges facing research in this field and how they can be addressed.

Thrombosis risk in single- and double-heterozygous carriers of factor V Leiden and prothrombin G20210A in FinnGen and the UK Biobank.

ABSTRACT: The factor V Leiden (FVL; rs6025) and prothrombin G20210A (PTGM; rs1799963) polymorphisms are 2 of the most well-studied genetic risk factors for venous thromboembolism (VTE). However, double heterozygosity (DH) for FVL and PTGM remains poorly understood, with previous studies showing marked disagreement regarding thrombosis risk conferred by the DH genotype. Using multidimensional data from the UK Biobank (UKB) and 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 with wild-type individuals (odds ratio [OR] = 5.24; 95% confidence interval [CI], 4.01-6.84; P = 4.8 × 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 × 10-16) after adjustment for commonly cited VTE risk factors, such as body mass index, blood type, and markers of inflammation. In 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 data sets to conduct, to our knowledge, the largest study to date on 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 may confer a similarly increased risk of VTE.

Monogenic and Polygenic Contributions to QTc Prolongation in the Population.

BACKGROUND: Rare sequence variation in genes underlying cardiac repolarization and common polygenic variation influence QT interval duration. However, current clinical genetic testing of individuals with unexplained QT prolongation is restricted to examination of monogenic rare variants. The recent emergence of large-scale biorepositories with sequence data enables examination of the joint contribution of rare and common variations to the QT interval in the population. METHODS: We performed a genome-wide association study of the QTc in 84 630 UK Biobank participants and created a polygenic risk score (PRS). Among 26 976 participants with whole-genome sequencing and ECG data in the TOPMed (Trans-Omics for Precision Medicine) program, we identified 160 carriers of putative pathogenic rare variants in 10 genes known to be associated with the QT interval. We examined QTc associations with the PRS and with rare variants in TOPMed. RESULTS: Fifty-four independent loci were identified by genome-wide association study in the UK Biobank. Twenty-one loci were novel, of which 12 were replicated in TOPMed. The PRS composed of 1 110 494 common variants was significantly associated with the QTc in TOPMed (ΔQTc/decile of PRS=1.4 ms [95% CI, 1.3 to 1.5]; P=1.1×10-196). Carriers of putative pathogenic rare variants had longer QTc than noncarriers (ΔQTc=10.9 ms [95% CI, 7.4 to 14.4]). Of individuals with QTc>480 ms, 23.7% carried either a monogenic rare variant or had a PRS in the top decile (3.4% monogenic, 21% top decile of PRS). CONCLUSIONS: QTc duration in the population is influenced by both rare variants in genes underlying cardiac repolarization and polygenic risk, with a sizeable contribution from polygenic risk. Comprehensive assessment of the genetic determinants of QTc prolongation includes incorporation of both polygenic and monogenic risk.

Lack of Evidence for the Role of the p.(Ser96Ala) Polymorphism in Histidine-Rich Calcium Binding Protein as a Secondary Hit in Cardiomyopathies.

Inherited forms of arrhythmogenic and dilated cardiomyopathy (ACM and DCM) are characterized by variable disease expression and age-related penetrance. Calcium (Ca2+) is crucially important for proper cardiac function, and dysregulation of Ca2+ homeostasis seems to underly cardiomyopathy etiology. A polymorphism, c.286T>G p.(Ser96Ala), in the gene encoding the histidine-rich Ca2+ binding (HRC) protein, relevant for sarcoplasmic reticulum Ca2+ cycling, has previously been associated with a marked increased risk of life-threatening arrhythmias among idiopathic DCM patients. Following this finding, we investigated whether p.(Ser96Ala) affects major cardiac disease manifestations in carriers of the phospholamban (PLN) c.40_42delAGA; p.(Arg14del) pathogenic variant (cohort 1); patients diagnosed with, or predisposed to, ACM (cohort 2); and DCM patients (cohort 3). We found that the allele frequency of the p.(Ser96Ala) polymorphism was similar across the general European-American population (control cohort, 40.3-42.2%) and the different cardiomyopathy cohorts (cohorts 1-3, 40.9-43.9%). Furthermore, the p.(Ser96Ala) polymorphism was not associated with life-threatening arrhythmias or heart failure-related events across various patient cohorts. We therefore conclude that there is a lack of evidence supporting the important role of the HRC p.(Ser96Ala) polymorphism as a modifier in cardiomyopathy, refuting previous findings. Further research is required to identify bona fide genomic predictors for the stratification of cardiomyopathy patients and their risk for life-threatening outcomes.

Monogenic and Polygenic Contributions to Atrial Fibrillation Risk: Results From a National Biobank.

RATIONALE: Genome-wide association studies have identified over 100 genetic loci for atrial fibrillation (AF); recent work described an association between loss-of-function (LOF) variants in TTN and early-onset AF. OBJECTIVE: We sought to determine the contribution of rare and common genetic variation to AF risk in the general population. METHODS: The UK Biobank is a population-based study of 500 000 individuals including a subset with genome-wide genotyping and exome sequencing. In this case-control study, we included AF cases and controls of genetically determined white-European ancestry; analyses were performed using a logistic mixed-effects model adjusting for age, sex, the first 4 principal components of ancestry, empirical relationships, and case-control imbalance. An exome-wide, gene-based burden analysis was performed to examine the relationship between AF and rare, high-confidence LOF variants in genes with ≥10 LOF carriers. A polygenic risk score for AF was estimated using the LDpred algorithm. We then compared the contribution of AF polygenic risk score and LOF variants to AF risk. RESULTS: The study included 1546 AF cases and 41 593 controls. In an analysis of 9099 genes with sufficient LOF variant carriers, a significant association between AF and rare LOF variants was observed in a single gene, TTN (odds ratio, 2.71, P=2.50×10-8). The association with AF was more significant (odds ratio, 6.15, P=3.26×10-14) when restricting to LOF variants located in exons highly expressed in cardiac tissue (TTNLOF). Overall, 0.44% of individuals carried TTNLOF variants, of whom 14% had AF. Among individuals in the highest 0.44% of the AF polygenic risk score only 9.3% had AF. In contrast, the AF polygenic risk score explained 4.7% of the variance in AF susceptibility, while TTNLOF variants only accounted for 0.2%. CONCLUSIONS: Both monogenic and polygenic factors contribute to AF risk in the general population. While rare TTNLOF variants confer a substantial AF penetrance, the additive effect of many common variants explains a larger proportion of genetic susceptibility to AF.

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.

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=8.0×10-4) 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.

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.

A diverse ancestrally-matched reference panel increases genotype imputation accuracy in a underrepresented population.

Variant imputation, a common practice in genome-wide association studies, relies on reference panels to infer unobserved genotypes. Multiple public reference panels are currently available with variations in size, sequencing depth, and represented populations. Currently, limited data exist regarding the performance of public reference panels when used in an imputation of populations underrepresented in the reference panel. Here, we compare the performance of various public reference panels: 1000 Genomes Project, Haplotype Reference Consortium, GenomeAsia 100 K, and the recent Trans-Omics for Precision Medicine (TOPMed) program, when used in an imputation of samples from the Thai population. Genotype yields were assessed, and imputation accuracies were examined by comparison with high-depth whole genome sequencing data of the same sample. We found that imputation using the TOPMed panel yielded the largest number of variants (~ 271 million). Despite being the smallest in size, GenomeAsia 100 K achieved the best imputation accuracy with a median genotype concordance rate of 0.97. For rare variants, GenomeAsia 100 K also offered the best accuracy, although rare variants were less accurately imputable than common variants (30.3% reduction in concordance rates). The high accuracy observed when using GenomeAsia 100 K is likely attributable to the diverse representation of populations genetically similar to the study cohort emphasizing the benefits of sequencing populations classically underrepresented in human genomics.

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.

Assessment of valvular function in over 47,000 people using deep learning-based flow measurements.

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.

Exploring the complex spectrum of dominance and recessiveness in genetic cardiomyopathies.

Discrete categorization of Mendelian disease genes into dominant and recessive models often oversimplifies their underlying genetic architecture. Cardiomyopathies (CMs) are genetic diseases with complex etiologies for which an increasing number of recessive associations have recently been proposed. Here, we comprehensively analyze all published evidence pertaining to biallelic variation associated with CM phenotypes to identify high-confidence recessive genes and explore the spectrum of monoallelic and biallelic variant effects in established recessive and dominant disease genes. We classify 18 genes with robust recessive association with CMs, largely characterized by dilated phenotypes, early disease onset and severe outcomes. Several of these genes have monoallelic association with disease outcomes and cardiac traits in the UK Biobank, including LMOD2 and ALPK3 with dilated and hypertrophic CM, respectively. Our data provide insights into the complex spectrum of dominance and recessiveness in genetic heart disease and demonstrate how such approaches enable the discovery of unexplored genetic associations.

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.

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.

Association of Rare Protein-Truncating DNA Variants in APOB or PCSK9 With Low-density Lipoprotein Cholesterol Level and Risk of Coronary Heart Disease.

Importance: Protein-truncating variants (PTVs) in apolipoprotein B (APOB) and proprotein convertase subtilisin/kexin type 9 (PCSK9) are associated with significantly lower low-density lipoprotein (LDL) cholesterol concentrations. The association of these PTVs with coronary heart disease (CHD) warrants further characterization in large, multiracial prospective cohort studies. Objective: To evaluate the association of PTVs in APOB and PCSK9 with LDL cholesterol concentrations and CHD risk. Design, Setting, and Participants: This studied included participants from 5 National Heart, Lung, and Blood Institute (NHLBI) studies and the UK Biobank. NHLBI study participants aged 5 to 84 years were recruited between 1971 and 2002 across the US and underwent whole-genome sequencing. UK Biobank participants aged 40 to 69 years were recruited between 2006 and 2010 in the UK and underwent whole-exome sequencing. Data were analyzed from June 2021 to October 2022. Exposures: PTVs in APOB and PCSK9. Main Outcomes and Measures: Estimated untreated LDL cholesterol levels and CHD. Results: Among 19 073 NHLBI participants (10 598 [55.6%] female; mean [SD] age, 52 [17] years), 139 (0.7%) carried an APOB or PCSK9 PTV, which was associated with 49 mg/dL (95% CI, 43-56) lower estimated untreated LDL cholesterol level. Over a median (IQR) follow-up of 21.5 (13.9-29.4) years, incident CHD was observed in 12 of 139 carriers (8.6%) vs 3029 of 18 934 noncarriers (16.0%), corresponding to an adjusted hazard ratio of 0.51 (95% CI, 0.28-0.89; P = .02). Among 190 464 UK Biobank participants (104 831 [55.0%] female; mean [SD] age, 57 [8] years), 662 (0.4%) carried a PTV, which was associated with 45 mg/dL (95% CI, 42-47) lower estimated untreated LDL cholesterol level. Estimated CHD risk by age 75 years was 3.7% (95% CI, 2.0-5.3) in carriers vs 7.0% (95% CI, 6.9-7.2) in noncarriers, corresponding to an adjusted hazard ratio of 0.51 (95% CI, 0.32-0.81; P = .004). Conclusions and Relevance: Among 209 537 individuals in this study, 0.4% carried an APOB or PCSK9 PTV that was associated with less exposure to LDL cholesterol and a 49% lower risk of CHD.

Selenoprotein deficiency disorder predisposes to aortic aneurysm formation.

Aortic aneurysms, which may dissect or rupture acutely and be lethal, can be a part of multisystem disorders that have a heritable basis. We report four patients with deficiency of selenocysteine-containing proteins due to selenocysteine Insertion Sequence Binding Protein 2 (SECISBP2) mutations who show early-onset, progressive, aneurysmal dilatation of the ascending aorta due to cystic medial necrosis. Zebrafish and male mice with global or vascular smooth muscle cell (VSMC)-targeted disruption of Secisbp2 respectively show similar aortopathy. Aortas from patients and animal models exhibit raised cellular reactive oxygen species, oxidative DNA damage and VSMC apoptosis. Antioxidant exposure or chelation of iron prevents oxidative damage in patient's cells and aortopathy in the zebrafish model. Our observations suggest a key role for oxidative stress and cell death, including via ferroptosis, in mediating aortic degeneration.

Genotype-Phenotype Taxonomy of Hypertrophic Cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is an important cause of sudden cardiac death associated with heterogeneous phenotypes, but there is no systematic framework for classifying morphology or assessing associated risks. Here, we quantitatively survey genotype-phenotype associations in HCM to derive a data-driven taxonomy of disease expression. METHODS: We enrolled 436 patients with HCM (median age, 60 years; 28.8% women) with clinical, genetic, and imaging data. An independent cohort of 60 patients with HCM from Singapore (median age, 59 years; 11% women) and a reference population from the UK Biobank (n=16 691; mean age, 55 years; 52.5% women) were also recruited. We used machine learning to analyze the 3-dimensional structure of the left ventricle from cardiac magnetic resonance imaging and build a tree-based classification of HCM phenotypes. Genotype and mortality risk distributions were projected on the tree. RESULTS: Carriers of pathogenic or likely pathogenic variants for HCM had lower left ventricular mass, but greater basal septal hypertrophy, with reduced life span (mean follow-up, 9.9 years) compared with genotype negative individuals (hazard ratio, 2.66 [95% CI, 1.42-4.96]; P<0.002). Four main phenotypic branches were identified using unsupervised learning of 3-dimensional shape: (1) nonsarcomeric hypertrophy with coexisting hypertension; (2) diffuse and basal asymmetrical hypertrophy associated with outflow tract obstruction; (3) isolated basal hypertrophy; and (4) milder nonobstructive hypertrophy enriched for familial sarcomeric HCM (odds ratio for pathogenic or likely pathogenic variants, 2.18 [95% CI, 1.93-2.28]; P=0.0001). Polygenic risk for HCM was also associated with different patterns and degrees of disease expression. The model was generalizable to an independent cohort (trustworthiness, M1: 0.86-0.88). CONCLUSIONS: We report a data-driven taxonomy of HCM for identifying groups of patients with similar morphology while preserving a continuum of disease severity, genetic risk, and outcomes. This approach will be of value in understanding the causes and consequences of disease diversity.

Large scale genome-wide association analyses identify novel genetic loci and mechanisms in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality with both monogenic and polygenic components. We here report results from the largest HCM genome-wide association study (GWAS) and multi-trait analysis (MTAG) including 5,900 HCM cases, 68,359 controls, and 36,083 UK Biobank (UKB) participants with cardiac magnetic resonance (CMR) imaging. We identified a total of 70 loci (50 novel) associated with HCM, and 62 loci (32 novel) associated with relevant left ventricular (LV) structural or functional traits. Amongst the common variant HCM loci, we identify a novel HCM disease gene, SVIL, which encodes the actin-binding protein supervillin, showing that rare truncating SVIL variants cause HCM. Mendelian randomization analyses support a causal role of increased LV contractility in both obstructive and non-obstructive forms of HCM, suggesting common disease mechanisms and anticipating shared response to therapy. Taken together, the findings significantly increase our understanding of the genetic basis and molecular mechanisms of HCM, with potential implications for disease management.

Rare and Common Genetic Variation Underlying the Risk of Hypertrophic Cardiomyopathy in a National Biobank.

Importance: Hypertrophic cardiomyopathy (HCM) is a leading cause of sudden cardiac death in young people. Although rare genetic variants are well-established contributors to HCM risk, common genetic variants have recently been implicated in disease pathogenesis. Objective: To assess the contributions of rare and common genetic variation to risk of HCM in the general population. Design, Setting, and Participants: This cohort study of the UK Biobank (data from 2006-2010) and the Mass General Brigham Biobank (2010-2019) assessed the relative and joint contributions of rare genetic variants and a common variant (polygenic) score to risk of HCM. Both rare and common variant predictors were then evaluated in the context of relevant clinical risk factors. Data analysis was conducted from May 2021 to February 2022. Exposures: Pathogenic rare variants, common-variant (polygenic) score, and clinical risk factors. Main Outcomes and Measures: Risk of HCM. Results: The primary study population comprised 184 511 individuals from the UK Biobank. Mean (SD) age was 56 (8) years, 83 690 (45%) of participants were men, and 204 (0.1%) participants had HCM. Of 51 genes included in clinical genetic testing panels for HCM, pathogenic or likely pathogenic variants in 14 core genes (designated by the American College of Medical Genetics and Genomics [ACMG]) were associated with 55-fold higher odds (95% CI, 35-83) of HCM, while those in the remaining 37 non-ACMG genes were not significantly associated with HCM (OR, 1.8; 95% CI, 0.6-4.0). ClinVar pathogenic or likely pathogenic mutations in MYBPC3 (OR, 72; 95% CI, 39-124) and MYH7 (OR, 61; 95% CI, 26-121) were strongly associated with HCM, as were loss-of-function variants in ALPK3 (OR, 13; 95% CI, 4.4-28). A polygenic score was strongly associated with HCM (OR per SD increase in score, 1.6; 95% CI, 1.4-1.8), with concordant results in the Mass General Brigham Biobank. Genetic factors enhanced clinical risk prediction for HCM: addition of rare variant carrier status and the polygenic score to clinical risk factors (obesity, hypertension, atrial fibrillation, and coronary artery disease) improved the area under the receiver operator characteristic curve from 0.71 (95% CI, 0.65-0.77) to 0.82 (95% CI, 0.77-0.87). Conclusions and Relevance: Both rare and common genetic variants contribute substantially to HCM susceptibility in the general population and improve HCM risk prediction beyond that achieved with clinical factors.