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Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect.

ABSTRACT: The heart muscle diseases hypertrophic (HCM) and dilated (DCM) cardiomyopathies are leading causes of sudden death and heart failure in young, otherwise healthy, individuals. We conducted genome-wide association studies and multi-trait analyses in HCM (1,733 cases), DCM (5,521 cases) and nine left ventricular (LV) traits (19,260 UK Biobank participants with structurally normal hearts). We identified 16 loci associated with HCM, 13 with DCM and 23 with LV traits. We show strong genetic correlations between LV traits and cardiomyopathies, with opposing effects in HCM and DCM. Two-sample Mendelian randomization supports a causal association linking increased LV contractility with HCM risk. A polygenic risk score explains a significant portion of phenotypic variability in carriers of HCM-causing rare variants. Our findings thus provide evidence that polygenic risk score may account for variability in Mendelian diseases. More broadly, we provide insights into how genetic pathways may lead to distinct disorders through opposing genetic effects.

SUBMITTER: Tadros R

PROVIDER: S-EPMC7611259 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect.

Tadros Rafik R Francis Catherine C Xu Xiao X Vermeer Alexa M C AMC Harper Andrew R AR Huurman Roy R Kelu Bisabu Ken K Walsh Roddy R Hoorntje Edgar T ET Te Rijdt Wouter P WP Buchan Rachel J RJ van Velzen Hannah G HG van Slegtenhorst Marjon A MA Vermeulen Jentien M JM Offerhaus Joost Allard JA Bai Wenjia W de Marvao Antonio A Lahrouchi Najim N Beekman Leander L Karper Jacco C JC Veldink Jan H JH Kayvanpour Elham E Pantazis Antonis A Baksi A John AJ Whiffin Nicola N Mazzarotto Francesco F Sloane Geraldine G Suzuki Hideaki H Schneider-Luftman Deborah D Elliott Paul P Richard Pascale P Ader Flavie F Villard Eric E Lichtner Peter P Meitinger Thomas T Tanck Michael W T MWT van Tintelen J Peter JP Thain Andrew A McCarty David D Hegele Robert A RA Roberts Jason D JD Amyot Julie J Dubé Marie-Pierre MP Cadrin-Tourigny Julia J Giraldeau Geneviève G L'Allier Philippe L PL Garceau Patrick P Tardif Jean-Claude JC Boekholdt S Matthijs SM Lumbers R Thomas RT Asselbergs Folkert W FW Barton Paul J R PJR Cook Stuart A SA Prasad Sanjay K SK O'Regan Declan P DP van der Velden Jolanda J Verweij Karin J H KJH Talajic Mario M Lettre Guillaume G Pinto Yigal M YM Meder Benjamin B Charron Philippe P de Boer Rudolf A RA Christiaans Imke I Michels Michelle M Wilde Arthur A M AAM Watkins Hugh H Matthews Paul M PM Ware James S JS Bezzina Connie R CR

Nature genetics 20210125 2

The heart muscle diseases hypertrophic (HCM) and dilated (DCM) cardiomyopathies are leading causes of sudden death and heart failure in young, otherwise healthy, individuals. We conducted genome-wide association studies and multi-trait analyses in HCM (1,733 cases), DCM (5,521 cases) and nine left ventricular (LV) traits (19,260 UK Biobank participants with structurally normal hearts). We identified 16 loci associated with HCM, 13 with DCM and 23 with LV traits. We show strong genetic correlatio ...[more]

PMID: 33495596

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Project description:Practical relevanceHypertrophic cardiomyopathy (HCM) is the most common form of feline cardiomyopathy observed clinically and may affect up to approximately 15% of the domestic cat population, primarily as a subclinical disease. Fortunately, severe HCM, leading to heart failure or arterial thromboembolism (ATE), only occurs in a small proportion of these cats.Patient groupDomestic cats of any age from 3 months upward, of either sex and of any breed, can be affected. A higher prevalence in male and domestic shorthair cats has been reported.DiagnosticsSubclinical feline HCM may or may not produce a heart murmur or gallop sound. Substantial left atrial enlargement can often be identified radiographically in cats with severe HCM. Biomarkers should not be relied on solely to diagnose the disease. While severe feline HCM can usually be diagnosed via echocardiography alone, feline HCM with mild to moderate left ventricular (LV) wall thickening is a diagnosis of exclusion, which means there is no definitive test for HCM in these cats and so other disorders that can cause mild to moderate LV wall thickening (eg, hyperthyroidism, systemic hypertension, acromegaly, dehydration) need to be ruled out.Key findingsWhile a genetic cause of HCM has been identified in two breeds and is suspected in another, for most cats the cause is unknown. Systolic anterior motion of the mitral valve (SAM) is the most common cause of dynamic left ventricular outflow tract obstruction (DLVOTO) and, in turn, the most common cause of a heart murmur with feline HCM. While severe DLVOTO is probably clinically significant and so should be treated, lesser degrees probably are not. Furthermore, since SAM can likely be induced in most cats with HCM, the distinction between HCM without obstruction and HCM with obstruction (HOCM) is of limited importance in cats. Diastolic dysfunction, and its consequences of abnormally increased atrial pressure leading to signs of heart failure, and sluggish atrial blood flow leading to ATE, is the primary abnormality that causes clinical signs and death in affected cats. Treatment (eg, loop diuretics) is aimed at controlling heart failure. Preventive treatment (eg, antithrombotic drugs) is aimed at reducing the risk of complications (eg, ATE).ConclusionsMost cats with HCM show no overt clinical signs and live a normal or near-normal life despite this disease. However, a substantial minority of cats develop overt clinical signs referable to heart failure or ATE that require treatment. For most cats with clinical signs caused by HCM, the long-term prognosis is poor to grave despite therapy.Areas of uncertaintyGenetic mutations (variants) that cause HCM have been identified in a few breeds, but, despite valiant efforts, the cause of HCM in the vast majority of cats remains unknown. No treatment currently exists that reverses or even slows the cardiomyopathic process in HCM, again despite valiant efforts. The search goes on.

Dataset Information

Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect.

Publications

Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect.

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