Contribution of rare genetic variants to heart failure and cardiomyopathy in the UK Biobank

Heart failure (HF) is a major global health burden.1 HF risk factors are hypertension, coronary heart disease, diabetes, obesity and valvular heart disease. HF aggregates in families and genome wide association studies have identified several HF variants.1 Cardiomyopathy is a relatively rare disease of the heart muscle and is one of many causes of HF. Cardiomyopathy is classified into dilated cardiomyopathy, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, and restrictive cardiomyopathy.2 Many genes and rare genetic variants have been linked to cardiomyopathy. Whether rare variants also are involved in HF is unknown.1 Few large-scale whole exome sequencing (WES) studies have been published until Wang et al. reported the relationships between rare protein-coding variants and 17 361 binary phenotypes using WES data from 269 171 UK Biobank participants (https://azphewas.com/).3 Gene-based collapsing analyses revealed 1703 statistically significant gene–phenotype associations for binary traits. Recently, Karczewski et al. also determined gene-based association investigating 4529 phenotypes in 394 841 UK Biobank exomes (https://app.genebass.org/).4 We used the two published UK Biobank portals (https://azphewas.com/ and https://app.genebass.org/)3, 4 to access gene-collapsing analysis of rare variation for HF and cardiomyopathy (Table 1). We therefore did not obtain ethical approval. The significance levels used in the two portals and published studies were stringent.3, 4 In order not to discard potential candidate genes, we present genes with P-vales <0.05/20 000 genes = 2.5 × 10−6 commonly used for WES studies. In Table 1, only the genes with genome wide significant results are shown with P-values for the best significant model. Four previously identified cardiomyopathy genes (TTN, MYH7, MYBPC3 and DSP) and one novel candidate cardiomyopathy gene (MAGOHB) were identified. Six novel genes were associated with common HF (TTN, FLNC, TET2, ASXL1, MYBPC3 and SEMA3G). TTN, MYBPC3 and FLNC genes have previously been linked to cardiomyopathy suggesting similar mechanisms to be involved in HF. SEMA3G has previously not been linked to any disease (https://varsome.com/ and https://www.omim.org/). TET2 and ASXL1 genes have been linked to myelodysplastic syndrome and mastocytosis (https://varsome.com/ and https://www.omim.org/). Interestingly, clonal haematopoiesis of indeterminate potential defined as clonally expanded leukemogenic sequence variations (in DNMT3A, TET2, ASXL1 and JAK2) have been associated with HF.5 TTN 2.16e-60a MYBPC3 7.28e-24a MYH7 3.40e-15a DSP 8.19e-11a MYBPC3 2.09e-27a DSP 2.11e-7a MYH7 4.12e-13a MAGOHB 3.51e-7 TTN 5.97e-27a FLNC 6.17e-7a TET2 6.54e-7b ASXL1 1.05e-6b In conclusion, five genes were associated with cardiomyopathy and six genes with HF in UK Biobank. This suggests that rare variation in several genes is linked both to cardiomyopathy and HF. Classical cardiomyopathy genes may be involved in heart failure. The association with TET2 and ASXL1 suggests clonal haematopoiesis of indeterminate potential might be involved in HF. This work was supported by a grant awarded to Dr Bengt Zöller by ALF funding from Region Skåne, Sparbanken Skåne, and by the Swedish Research Council.