Authors
Sean J Jurgens, Nobuyuki Enzan, Ian R Dinsmore, Seung Hoan Choi, Jon Luo, Alex Lipov, Cassandra Hartle, Xin Wang, Nicholas A Marston, Lu-Chen Weng, Giorgio Em Melloni, Brandon Chalazan, Michael P Gray, James P Pirruccello, Annette Diaz, Mark D Chaffin, Aylin Ornelas-Loredo, Owen Tang, Faisal A Darbar, Shinwan Kany, Yining Chen, Aenne S von Falkenhausen, Alanna C Morrison, Andrea Natale, Arnljot Tveit, Bastiaan Geelhoed, Brian Cade, David R Van Wagoner, Doreen Haase, Elsayed Z Soliman, Giovanni E Davogustto, Hugh Calkins, Jeffrey L Anderson, Jennifer A Brody, John Barnard, John E Hokanson, Jonathan D Smith, Joshua C Bis, Kendra Young, Linda Sb Johnson, Leann Long, Lorenz Risch, Lorne J Gula, Lydia Coulter Kwee, Michael Kühne, Michael Preuss, Namrata Gupta, Navid A Nafissi, Nicholas L Smith, Peter M Nilsson, Pim van der Harst, Quinn S Wells, Renae L Judy, Renate B Schnabel, Renee Johnson, Roelof Aj Smit, Stacey Gabriel, Stacey Knight, Tetsushi Furukawa, Yuan-I Min, Zachary T Yoneda, Zachary Wm Laksman, Alvaro Alonso, Bruce M Psaty, Christine M Albert, Dan E Arking, Dan M Roden, Daniel I Chasman, Daniel J Rader, David Conen, David D McManus, Diane Fatkin, Eric Boerwinkle, Gregory M Marcus, Ingrid E Christophersen, J Gustav Smith, Jason D Roberts, Laura M Raffield, M Benjamin Shoemaker, Michael H Cho, Michael J Cutler, Mina K Chung, Morten S Olesen, Moritz F Sinner, Nona Sotoodehnia, Paulus Kirchhof, Ruth Jf Loos, Saman Nazarian, Sanghamitra Mohanty, Scott M Damrauer, Stefan Kaab, Susan R Heckbert, Susan Redline, Svati H Shah, Toshihiro Tanaka, Yusuke Ebana, Regeneron Genetics Center, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Steven A Lubitz, Kathryn L Lunetta, Emelia J Benjamin, Michiel Rienstra, Gemma A Figtree, Dawood Darbar, Connie R Bezzina, Christian T Ruff, Marc S Sabatine, Tooraj Mirshahi, Patrick T Ellinor
Published in
Research square. May 04, 2026. Epub May 04, 2026.
Abstract
Rare coding genetic variants may exert large effects on risk of common disease, yet their contribution to disease architecture and their utility in gene prioritization remain limited by inadequate sample sizes. Here, we performed a massive-scale rare variant association study (RVAS), analyzing over 1.1 million sequenced participants among which 130,000 had atrial fibrillation (AF). Through a multi-mask burden testing approach, we identified 15 genes significantly associated with AF through rare large-effect variation. Integrative analyses revealed strong convergence between genes implicated by rare and common variation, and highlighted instances where RVAS data may aid in GWAS prioritization. Nevertheless, several RVAS genes were not among GWAS loci (FAM189A2, ACTC1, FNIP1, FBN1), or were not nominated through contemporary GWAS prioritization (KDM5B, ZFP36L2). Finally, we observed that ultra-rare protein-disrupting variants - concentrated in a small number of large-effect size genes - explained at least 2% of AF susceptibility across European and African ancestry groups. These findings refine the genetic architecture of AF, while highlighting the value and cost of RVAS for genomic discovery in common disease.
PMID:
42147184
Bibliographic data and abstract were imported from PubMed on 15 Sep 2026.
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