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
Over 35% of all adults in the world are currently obese and risk of obesity in racial or ethnic minority groups exist in the US, but the causes of these differences are not all known. As obesity is a Show more
Over 35% of all adults in the world are currently obese and risk of obesity in racial or ethnic minority groups exist in the US, but the causes of these differences are not all known. As obesity is a leading cause of cardiovascular disease, an improved understanding of risk factors across racial and ethnic groups may improve outcomes. The objective of this study was to determine if susceptibility to obesity is associated with genetic variation in candidate single nucleotide polymorphisms (SNPs) in African Americans and Hispanic/Latinos. We examined data from 534 African Americans and 557 Hispanic/Latinos participants from the UIC Cohort of Patients, Family and Friends. Participants were genotyped for the top 26 obesity-associated SNPs within FTO, MC4R, TUB, APOA2, APOA5, ADIPOQ, ARL15, CDH13, KNG1, LEPR, leptin, and SCG3 genes. The mean (SD) age of participants was 49±13 years, 55% were female, and mean body mass index (BMI) was 31±7.5 kg/m2. After adjusting for age and sex, we found that rs8050136 in FTO (odds ratio [OR] 1.40, 95% confidence interval [CI] 1.1-1.8; P = 0.01) among African Americans and rs2272383 in TUB (OR 1.34, 95% CI 1.04-1.71; P = 0.02) among Hispanic/Latinos were associated with obesity. However, none of the SNPs in multivariable analysis of either AA or H/L cohorts were significant when adjusted for multiple correction. We show that candidate SNPs in the FTO and TUB genes are associated with obesity in African Americans and Hispanic/Latinos individuals respectively. While the underlying pathophysiological mechanisms by which common genetic variants cause obesity remain unclear, we have identified novel therapeutic targets across racial and ethnic groups. Show less