👤 David R Van Wagoner

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

Coronary artery disease (CAD) remains a leading cause of disease burden globally, and there is a persistent need for new therapeutic targets. Instrumental variable (IV) and genetic colocalization analyses can help identify novel therapeutic targets for human disease by nominating causal genes in genome-wide association study (GWAS) loci. We conducted cis-IV analyses for 20,125 genes and 1,746 plasma proteins with CAD using molecular trait quantitative trait loci variant (QTLs) data from three different studies. 19 proteins and 119 genes were significantly associated with CAD risk by IV analyses and demonstrated evidence of genetic colocalization. Notably, our analyses validated well-established targets such as PCSK9 and ANGPTL4 while also identifying HTRA1 and endotrophin (a cleavage product of COL6A3) as proteins whose levels are causally associated with CAD risk. Further experimental studies are needed to confirm the causal role of the genes and proteins identified through our multiomic cis-IV analyses on human disease. Show less

Many biomedical engineering degree programs lack substantial immersive clinical experiences for undergraduate students, creating a need for clinical immersion programs that contribute to training objectives that emphasize current clinical needs (Becker in Eur J Eng Educ 31:261-272, 2006; Davis et al. in J Eng Educ 91:211-221, 2002; Dym et al. in J Eng Educ 94:103-120, 2005). Immersive clinical experiences have the potential to bridge the gap between clinical and non-clinical learning objectives in biomedical engineering curriculum. In collaboration with Indiana University Health Methodist Hospital, we have created, executed, and evaluated a two-week cardiovascular clinical immersion program for biomedical engineering undergraduate students at Purdue University. As of August 2022, this program has run 11 times since 2014 with 60 participants to date, exposing students to intensive and non-intensive care environments, facilitating interactions with medical professionals, and encouraging exploration of innovative technologies shaping the training of clinicians with direct patient interaction. The variety of cardiovascular topics discussed and clinical settings observed has provided students with a unique, highly beneficial learning opportunity. Keys to the continued success and growth of similar programs include: recruiting a diverse team, support from administrative staff/clinicians, a funded student intern position, and careful consideration of liability/risk management. Areas of future consideration include, streamlining the order of scheduled events, determining if offering course credit would be beneficial to students, and tracking career trajectories after participations. Show less