Atrial fibrillation (AF) is a prevalent and morbid abnormality of the heart rhythm with a strong genetic component. Here, we meta-analyzed genome and exome sequencing data from 36 studies that include Show more
Atrial fibrillation (AF) is a prevalent and morbid abnormality of the heart rhythm with a strong genetic component. Here, we meta-analyzed genome and exome sequencing data from 36 studies that included 52,416 AF cases and 277,762 controls. In burden tests of rare coding variation, we identified novel associations between AF and the genes MYBPC3, LMNA, PKP2, FAM189A2 and KDM5B. We further identified associations between AF and rare structural variants owing to deletions in CTNNA3 and duplications of GATA4. We broadly replicated our findings in independent samples from MyCode, deCODE and UK Biobank. Finally, we found that CRISPR knockout of KDM5B in stem-cell-derived atrial cardiomyocytes led to a shortening of the action potential duration and widespread transcriptomic dysregulation of genes relevant to atrial homeostasis and conduction. Our results highlight the contribution of rare coding and structural variants to AF, including genetic links between AF and cardiomyopathies, and expand our understanding of the rare variant architecture for this common arrhythmia. Show less
The role of biomarkers in diagnosing pulmonary hypertension (PH) and distinguishing between pre- and post-capillary PH remains poorly understood. We aimed to identify biomarkers with a strong associat Show more
The role of biomarkers in diagnosing pulmonary hypertension (PH) and distinguishing between pre- and post-capillary PH remains poorly understood. We aimed to identify biomarkers with a strong association with mean pulmonary arterial pressure, mPAP (PH diagnosis) and pulmonary vascular resistance, PVR (pre-capillary component), but not with pulmonary arterial wedge pressure, PAWP (post-capillary component). Blood samples were collected in patients undergoing right heart catheterization within a prospective cross-sectional study. Biomarkers measured included BMP10, NT-proBNP, ANG2, ESM1/endocan, FGF23, GDF15, IGFBP7, IL6, MyBPC3, proC3, and proC6/endotrophin. Primary outcomes were mPAP, PVR, and PAWP, while secondary outcomes included PH diagnosis (mPAP > 20 mmHg) and elevated PVR (> 2 Wood units). Multivariable linear and logistic regression models were used to assess the relationship between biomarkers and outcomes. Of the 127 patients included (age 66 ± 13 years, 54% female), 73% were diagnosed with PH. BMP10, NT-proBNP, ANG2, MyBPC3, and FGF23 showed a strong association with mPAP (p < 0.001). BMP10 and NT-proBNP were strongly associated with PVR (p < 0.001), while NT-proBNP and ANG2 were strongly associated with PAWP (p < 0.001). NT-proBNP had the strongest association with the diagnosis of PH (area under the curve = 0.76). BMP10 was the only biomarker associated with elevated PVR (OR 1.60, 95%CI 1.01-2.54, p = 0.04) but not with PAWP (p = 0.86). Several biomarkers were strongly associated with mPAP, PAWP, and PVR. BMP10 was the only biomarker strongly associated with mPAP and PVR, but not with PAWP, thus reflecting the pre-capillary PH component. Measurement of BMP10 along with NT-proBNP may aid in diagnosing PH. Show less