Genome-wide association and multi-trait analyses characterize the common genetic architecture of heart failure

Levin, Michael G.; Tsao, Noah; Singhal, Pankhuri; Liu, Chang; Vy, Ha My T.; Paranjpe, Ishan; Backman, Joshua; Bellomo, Tiffany; Bone, William P.; Biddinger, Kiran J; Hui, Qin; Dikilitas, Ozan; Satterfield, Benjamin A.; Yang, Yifan; Morley, Michael; Bradford, Yuki; Burke, Megan F.; Reza, Nosheen; Charest, Brian; Judy, Renae; Puckelwartz, Megan J.; Hákonarson, Hákon; Khan, Atlas; Kottyan, Leah C.; Kullo, Iftikhar J.; Luo, Yuan; McNally, Elizabeth M.; Rasmussen‐Torvik, Laura J.; Day, Sharlene M.; Do, Ron; Phillips, Lawrence S.; Ellinor, Patrick T.; Nadkarni, Girish N.; Ritchie, Marylyn D.; Arany, Zoltàn; Cappola, Thomas P.; Margulies, Kenneth B.; Aragam, Krishna; Haggerty, Christopher M.; Joseph, Jacob; Sun, Yan V.; Voight, Benjamin F.; Damrauer, Scott M.

doi:10.1038/s41467-022-34216-6

Cited by 37 publications

(40 citation statements)

References 107 publications

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“…Our results showed that BCAA/BCKA accumulation was prominent in heart tissue following BCAA challenge, consistent with a detrimental effect from elevated BCAA/BCKA level for cardiomyocyte function. Our result is also supported by a recent GWAS study where a meta analysis has identified a total of 47 risk loci associated with heart failure [33]. Among them, colocalization, gene expression profiling as well as Mendelian randomization provided convergent evidence for the roles of BCKDHA and circulating branched-chain amino acids in heart failure and cardiac structure, providing additional genetic evidence that BCKDHA plays a critical role in human heart failure development.…”

Section: Discussionsupporting

confidence: 81%

Cell-autonomous effect of cardiomyocyte branched-chain amino acid catabolism in heart failure in mice

Cao

Rau

et al. 2023

Acta Pharmacol Sin

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Parallel to major changes in fatty acid and glucose metabolism, defect in branched-chain amino acid (BCAA) catabolism has also been recognized as a metabolic hallmark and potential therapeutic target for heart failure. However, BCAA catabolic enzymes are ubiquitously expressed in all cell types and a systemic BCAA catabolic defect is also manifested in metabolic disorder associated with obesity and diabetes. Therefore, it remains to be determined the cell-autonomous impact of BCAA catabolic defect in cardiomyocytes in intact hearts independent from its potential global effects. In this study, we developed two mouse models. One is cardiomyocyte and temporal-specific inactivation of the E1α subunit (BCKDHA-cKO) of the branched-chain α-ketoacid dehydrogenase (BCKDH) complex, which blocks BCAA catabolism. Another model is cardiomyocyte specific inactivation of the BCKDH kinase (BCKDK-cKO), which promotes BCAA catabolism by constitutively activating BCKDH activity in adult cardiomyocytes. Functional and molecular characterizations showed E1α inactivation in cardiomyocytes was sufficient to induce loss of cardiac function, systolic chamber dilation and pathological transcriptome reprogramming. On the other hand, inactivation of BCKDK in intact heart does not have an impact on baseline cardiac function or cardiac dysfunction under pressure overload. Our results for the first time established the cardiomyocyte cell autonomous role of BCAA catabolism in cardiac physiology. These mouse lines will serve as valuable model systems to investigate the underlying mechanisms of BCAA catabolic defect induced heart failure and to provide potential insights for BCAA targeted therapy.

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Section: Discussionsupporting

confidence: 81%

Cell-autonomous effect of cardiomyocyte branched-chain amino acid catabolism in heart failure in mice

Cao

Rau

et al. 2023

Acta Pharmacol Sin

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“…Genome-wide association studies (GWAS) of heart failure (HF) and cardiac traits have begun to yield important translational insights, however, existing studies are limited by phenotypic heterogeneity and a lack of stratification by major aetiologies [1][2][3] . To address these limitations, we performed a GWAS meta-analysis of 153,174 HF cases in 1.9 million ancestrally diverse individuals, including analysis of 4 HF subtypes defined by aetiology and left ventricular ejection fraction (Supplementary Figure 1).…”

Section: Mainmentioning

confidence: 99%

“…GWAS of ni-HF, ni-HFrEF, and ni-HFpEF subtypes highlighted 10 additional sentinel variants that were not identified in the HF GWAS. In total, 66 independent genomic risk loci were identified across HF phenotypes 1,4,5 among which 37 have not previously been reported in GWAS of HF [1][2][3][4][5] . Of the 66 loci, 46 (70%) were associated with at least one of the non-ischaemic HF phenotypes at P < 0.05 / 66.…”

Section: Multi-ancestry Genetic Association Analysis Highlights Novel...mentioning

confidence: 99%

Mapping the aetiological foundations of the heart failure spectrum using human genetics

Henry,

Mo,

Finan

et al. 2023

Preprint

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Summary paragraphHeart failure (HF), a syndrome of symptomatic fluid overload due to cardiac dysfunction, is the most rapidly growing cardiovascular disorder. Despite recent advances, mortality and morbidity remain high and treatment innovation is challenged by limited understanding of aetiology in relation to disease subtypes. Here we harness the de-confounding properties of genetic variation to map causal biology underlying the HF phenotypic spectrum, to inform the development of more effective treatments. We report a genetic association analysis in 1.9 million ancestrally diverse individuals, including 153,174 cases of HF; 44,012 of non-ischaemic HF; 5,406 cases of non-ischaemic HF with reduced ejection fraction (HFrEF); and 3,841 cases of non-ischaemic HF with preserved ejection fraction (HFpEF). We identify 66 genetic susceptibility loci across HF subtypes, 37 of which have not previously been reported. We map the aetiologic contribution of risk factor traits and diseases as well as newly identified effector genes for HF, demonstrating differential risk factor effects on disease subtypes. Our findings highlight the importance of extra-cardiac tissues in HF, particularly the kidney and the vasculature in HFpEF. Pathways of cellular senescence and proteostasis are notably uncovered, includingIGFBP7as an effector gene for HFpEF. Using population approaches causally anchored in human genetics, we provide fundamental new insights into the aetiology of heart failure subtypes that may inform new approaches to prevention and treatment.

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“…Data sources and genetic instrumental variables selection for cardiovascular diseases (Table 1) Heart failure As to heart failure, GWAS summary level data was obtained from the most comprehensive GWAS in a metaanalysis across the Heart Failure Molecular Epidemiology for Therapeutic Targets, which included about a million European participants (47,309 cases and 930,014 controls) [23]. In the reverse MR analysis, a total of 47 independent SNPs were identi ed at a genome-wide signi cant threshold among 1,665,481 subjects (115,150 cases and 1,550,331 controls) and used as IVs [24].…”

Section: Data Sources and Genetic Instrumental Variables Selection Fo...mentioning

confidence: 99%

The causal association between primary aldosteronism and cardiovascular diseases: a bidirectional two-sample Mendelian randomization study

Shi

Zhang

et al. 2023

Preprint

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Background Many previous observational studies have shown that primary aldosteronism (PA) can increase the risk of cardiovascular diseases (CVDs), but the causal relationship is unclear. Methods We performed a bidirectional two-sample Mendelian randomization (MR) analysis to explore the causal association between PA and CVDs using summary statistics from the large publicly accessible genome-wide association study (GWAS) of PA (Ncases=1,724, Ncontrols=4,246) as well as six types of CVDs. Moreover, the inverse variance weighted (IVW) was used as the main method in MR analysis, and sensitivity analysis was further performed. Results Our results from the IVW analysis showed that genetically predicated PA conferred an increased risk of heart failure [odds ratio (OR) = 1.027, 95% confidence interval (CI): 1.013–1.041, p = 1.452×10− 4], atrial fibrillation (OR = 1.066, 95%CI: 1.051–1.082, p = 2.835×10− 17), hypertension (OR = 1.163, 95%CI: 1.105–1.223, p = 4.752×10− 9), coronary artery disease (OR = 1.032, 95%CI: 1.022–1.043, p = 1.664×10− 9), stroke (OR = 1.060, 95%CI: 1.044–1.075, p = 2.270×10− 15), myocardial infarction (OR = 1.020, 95%CI: 1.001–1.039, p = 0.044). However, with the exception of hypertension (OR = 3.316, 95%CI: 1.347–8.159, p = 0.009), CVDs leading to PA were not confirmed in reverse causality analysis. The sensitivity analysis showed the robustness of the results. Conclusion It is confirmed from the genetic level that there is a causal relationship between PA and CVDs and also confirmed that PA and hypertension are mutually causal. Our work highlights the necessity of routine screening, diagnosis and treatment of PA.

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Genome-wide association and multi-trait analyses characterize the common genetic architecture of heart failure

Cited by 37 publications

References 107 publications

Cell-autonomous effect of cardiomyocyte branched-chain amino acid catabolism in heart failure in mice

Cell-autonomous effect of cardiomyocyte branched-chain amino acid catabolism in heart failure in mice

Mapping the aetiological foundations of the heart failure spectrum using human genetics

The causal association between primary aldosteronism and cardiovascular diseases: a bidirectional two-sample Mendelian randomization study

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