Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity

Harper, Andrew R.; Goel, Anuj; Grace, Christopher; Thomson, Kate; Petersen, Steffen E.; Xu, Xiaowei; Waring, Adam; Ormondroyd, Elizabeth; Kramer, Christopher M.; Ho, Carolyn Y.; Neubauer, Stefan; Tadros, Rafik; Ware, James S.; Bezzina, Connie R.; Farrall, Martin; Watkins, Hugh

doi:10.1038/s41588-020-00764-0

Cited by 199 publications

(248 citation statements)

References 70 publications

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“…We have previously shown that the presence of the common variant HNF1A p.(I27L) reduces the age of diagnosis of HNF1A MODY 32 . Recent studies of monogenic cardiomyopathy, familial hypercholesterolemia and monogenic breast cancer also observed the impact of common variants on the phenotype [33][34][35] . Despite the relatively large size of our cohorts, we were limited by small numbers of carriers of individual pathogenic variants and were unable to evaluate modifiers.…”

Section: Discussionmentioning

confidence: 99%

The penetrance of age-related monogenic disease depends on ascertainment context

Mirshahi

Colclough

Wright

et al. 2021

Preprint

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BACKGROUND: Accurate penetrance of monogenic disorders is often unknown due to a phenotype-first approach to genetic testing. Here, we use a genotype-first approach in four large cohorts with different ascertainment contexts to accurately estimate penetrance of the three commonest causes of monogenic diabetes, Maturity Onset Diabetes of the Young (MODY). We contrast HNF1A-MODY / HNF4A-MODY which causes an age-related progressive diabetes and GCK-MODY, which causes life-long mild hyperglycaemia. METHODS: We analysed clinical and genetic sequencing data from four different cohorts: 1742 probands referred for clinical MODY testing; 2194 family members of the MODY probands; 132,194 individuals from an American hospital-based cohort; and 198,748 individuals from a UK population-based cohort. RESULTS: Age-related penetrance of diabetes for pathogenic variants in HNF1A and HNF4A was substantially lower in the clinically unselected cohorts compared to clinically referred probands (ranging from 32% to 98% at age 40yrs for HNF1A, and 21% to 99% for HNF4A). The background rate of diabetes, but not clinical features or variant type, explained the reduced penetrance in the unselected cohorts. In contrast, penetrance of mild hyperglycaemia for pathogenic GCK variants was similarly high across cohorts (ranging from 89 to 97%) despite substantial variation in the background rates of diabetes. CONCLUSIONS: Ascertainment context is crucial when interpreting the consequences of monogenic variants for age-related variably penetrant disorders. This finding has important implications for opportunistic screening during genomic testing.

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Section: Discussionmentioning

confidence: 99%

The penetrance of age-related monogenic disease depends on ascertainment context

Mirshahi

Colclough

Wright

et al. 2021

Preprint

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“…Tadros et al described left ventricular (LV) trait as one of such host factors with HCM-enforcing effects positively associated with LV wall thickness and LV ejection fraction while DCM-enforcing effects correlated with increased LV end systolic and end diastolic volumes. Furthermore, elevated diastolic pressure represents yet another substantial risk for developing HCM [20]. Collectively, these studies convincingly demonstrated the polygenic nature of HCM pathogenesis and revealed the complex interaction between common variants and modifiable host factors in modulating HCM disease progression.…”

Section: Genetic and Non-genetic Risk Modifiersmentioning

confidence: 68%

“…Notably, a polygenic risk score derived from such common variants after excluding sarcomere mutations stratifies disease-free survival in carriers of pathogenic or likely pathogenic sarcomere mutations. In support of this, another GWAS study by Harper et al identified similar common variants in sarcomere mutation negative HCM patients from which a risk score was derived and used to predict phenotypic severity in sarcomere variant carriers [20]. These two seminal studies thus provide the first evidence that a polygenic risk score based on HCM susceptibility variants may explain the interpersonal variability in disease severity among carriers of rare disease-causing variants.…”

Section: Genetic and Non-genetic Risk Modifiersmentioning

confidence: 87%

Pathogenic Mechanisms of Hypertrophic Cardiomyopathy Beyond Sarcomere Dysfunction

Chou

Chin

2021

Preprint

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Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disorder affecting 1 in 500 people in the general population. Although characterized by asymmetric left ventricular hypertrophy, cardiomyocyte disarray and cardiac fibrosis, HCM is in fact a highly complex disease with heterogenous clinical presentation, onset and complications. While HCM is generally accepted as a disease of the sarcomere, variable penetrance in families with identical genetic mutations challenges the monogenic origin of HCM and instead implies a multifactorial cause. Furthermore, large scale genome sequencing studies revealed that many genes previously reported as causative of HCM in fact have little or no evidence of disease association. These findings thus call for a re-evaluation of the sarcomere-centered view of HCM pathogenesis. Here, we summarize our current understanding of sarcomere-independent mechanisms of cardiomyocyte hypertrophy, highlight the role of extracellular signals in cardiac fibrosis, and propose an alternative but integrated model of HCM pathogenesis.

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“…Detailed results are provided in Supplementary Table 7 and Supplementary Table 8 We identified common variants within genes implicated in cardiomyopathies (e.g. BAG3, FHOD3, PLN), suggesting sarcomere homeostasis during mechanical stress may affect diastolic function in both health and disease 37 . A further example is the identification of the gene of a key regulator of cardiac diastolic function, phospholamban (PLN), which modulates sarcoplasmic reticulum calcium-ATPase activity 38 .…”

Section: /23mentioning

confidence: 99%

Genetic and environmental determinants of diastolic heart function

Thanaj

Mielke

et al. 2021

Preprint

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Diastole is the sequence of physiological events that occur in the heart during ventricular filling and principally depends on myocardial relaxation and chamber stiffness. Abnormal diastolic function is related to many cardiovascular disease processes and is predictive of health outcomes, but its genetic architecture is largely unknown. Here, we use machine learning cardiac motion analysis to measure diastolic functional traits in 39,559 participants of UK Biobank and perform a genome-wide association study. We identified 9 significant, independent loci near genes that are associated with maintaining sarcomeric function under biomechanical stress and genes implicated in the development of cardiomyopathy. Age, sex and diabetes were independent predictors of diastolic function and we found a causal relationship between ventricular stiffness and heart failure. Our results provide novel insights into the genetic and environmental factors influencing diastolic function that are relevant for identifying causal relationships and tractable targets in heart failure.

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Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity

Cited by 199 publications

References 70 publications

The penetrance of age-related monogenic disease depends on ascertainment context

The penetrance of age-related monogenic disease depends on ascertainment context

Pathogenic Mechanisms of Hypertrophic Cardiomyopathy Beyond Sarcomere Dysfunction

Genetic and environmental determinants of diastolic heart function

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