Rare coding variant architecture and gene discovery from 130,000 sequenced cases of atrial fibrillation.
Jurgens Sean J, Enzan Nobuyuki, Dinsmore Ian R, Choi Seung Hoan, Luo Jon, Lipov Alex, Hartle Cassandra, Wang Xin, Marston Nicholas A, Weng Lu-Chen, Melloni Giorgio Em, Chalazan Brandon, Gray Michael P, Pirruccello James P, Diaz Annette, Chaffin Mark D, Ornelas-Loredo Aylin, Tang Owen, Darbar Faisal A, Kany Shinwan, Chen Yining, von Falkenhausen Aenne S, Morrison Alanna C, Natale Andrea, Tveit Arnljot, Geelhoed Bastiaan, Cade Brian, Van Wagoner David R, Haase Doreen, Soliman Elsayed Z, Davogustto Giovanni E, Calkins Hugh, Anderson Jeffrey L, Brody Jennifer A, Barnard John, Hokanson John E, Smith Jonathan D, Bis Joshua C, Young Kendra, Johnson Linda Sb, Long Leann, Risch Lorenz, Gula Lorne J, Kwee Lydia Coulter, Kühne Michael, Preuss Michael, Gupta Namrata, Nafissi Navid A, Smith Nicholas L, Nilsson Peter M, van der Harst Pim, Wells Quinn S, Judy Renae L, Schnabel Renate B, Johnson Renee, Smit Roelof Aj, Gabriel Stacey, Knight Stacey, Furukawa Tetsushi, Min Yuan-I, Yoneda Zachary T, Laksman Zachary Wm, Alonso Alvaro, Psaty Bruce M, Albert Christine M, Arking Dan E, Roden Dan M, Chasman Daniel I, Rader Daniel J, Conen David, McManus David D, Fatkin Diane, Boerwinkle Eric, Marcus Gregory M, Christophersen Ingrid E, Smith J Gustav, Roberts Jason D, Raffield Laura M, Shoemaker M Benjamin, Cho Michael H, Cutler Michael J, Chung Mina K, Olesen Morten S, Sinner Moritz F, Sotoodehnia Nona, Kirchhof Paulus, Loos Ruth Jf, Nazarian Saman, Mohanty Sanghamitra, Damrauer Scott M, Kaab Stefan, Heckbert Susan R, Redline Susan, Shah Svati H, Tanaka Toshihiro, Ebana Yusuke, Regeneron Genetics Center, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Lubitz Steven A, Lunetta Kathryn L, Benjamin Emelia J, Rienstra Michiel, Figtree Gemma A, Darbar Dawood, Bezzina Connie R, Ruff Christian T, Sabatine Marc S, Mirshahi Tooraj, Ellinor Patrick T
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Аннотация
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.
Для цитирования: Jurgens Sean J, Enzan Nobuyuki, Dinsmore Ian R, Choi Seung Hoan, Luo Jon, Lipov Alex, Hartle Cassandra, Wang Xin, Marston Nicholas A, Weng Lu-Chen, Melloni Giorgio Em, Chalazan Brandon, Gray Michael P, Pirruccello James P, Diaz Annette, Chaffin Mark D, Ornelas-Loredo Aylin, Tang Owen, Darbar Faisal A, Kany Shinwan, Chen Yining, von Falkenhausen Aenne S, Morrison Alanna C, Natale Andrea, Tveit Arnljot, Geelhoed Bastiaan, Cade Brian, Van Wagoner David R, Haase Doreen, Soliman Elsayed Z, Davogustto Giovanni E, Calkins Hugh, Anderson Jeffrey L, Brody Jennifer A, Barnard John, Hokanson John E, Smith Jonathan D, Bis Joshua C, Young Kendra, Johnson Linda Sb, Long Leann, Risch Lorenz, Gula Lorne J, Kwee Lydia Coulter, Kühne Michael, Preuss Michael, Gupta Namrata, Nafissi Navid A, Smith Nicholas L, Nilsson Peter M, van der Harst Pim, Wells Quinn S, Judy Renae L, Schnabel Renate B, Johnson Renee, Smit Roelof Aj, Gabriel Stacey, Knight Stacey, Furukawa Tetsushi, Min Yuan-I, Yoneda Zachary T, Laksman Zachary Wm, Alonso Alvaro, Psaty Bruce M, Albert Christine M, Arking Dan E, Roden Dan M, Chasman Daniel I, Rader Daniel J, Conen David, McManus David D, Fatkin Diane, Boerwinkle Eric, Marcus Gregory M, Christophersen Ingrid E, Smith J Gustav, Roberts Jason D, Raffield Laura M, Shoemaker M Benjamin, Cho Michael H, Cutler Michael J, Chung Mina K, Olesen Morten S, Sinner Moritz F, Sotoodehnia Nona, Kirchhof Paulus, Loos Ruth Jf, Nazarian Saman, Mohanty Sanghamitra, Damrauer Scott M, Kaab Stefan, Heckbert Susan R, Redline Susan, Shah Svati H, Tanaka Toshihiro, Ebana Yusuke, Regeneron Genetics Center, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Lubitz Steven A, Lunetta Kathryn L, Benjamin Emelia J, Rienstra Michiel, Figtree Gemma A, Darbar Dawood, Bezzina Connie R, Ruff Christian T, Sabatine Marc S, Mirshahi Tooraj, Ellinor Patrick T. Rare coding variant architecture and gene discovery from 130,000 sequenced cases of atrial fibrillation.. Research square. 2026. DOI: 10.21203/rs.3.rs-9191644/v1.
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