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DOI 10.1038/s41588-024-01975-5

Медицинская библиотека · Nature genetics · 2024

Genome-wide association study reveals mechanisms underlying dilated cardiomyopathy and myocardial resilience.

Jurgens Sean J, Rämö Joel T, Kramarenko Daria R, Wijdeveld Leonoor F J M, Haas Jan, Chaffin Mark D, Garnier Sophie, Gaziano Liam, Weng Lu-Chen, Lipov Alex, Zheng Sean L, Henry Albert, Huffman Jennifer E, Challa Saketh, Rühle Frank, Verdugo Carmen Diaz, Krijger Juárez Christian, Kany Shinwan, van Orsouw Constance A, Biddinger Kiran, Poel Edwin, Elliott Amanda L, Wang Xin, Francis Catherine, Ruan Richard, Koyama Satoshi, Beekman Leander, Zimmerman Dominic S, Deleuze Jean-François, Villard Eric, Trégouët David-Alexandre, Isnard Richard, FinnGen, VA Million Veteran Program, HERMES Consortium, Boomsma Dorret I, de Geus Eco J C, Tadros Rafik, Pinto Yigal M, Wilde Arthur A M, Hottenga Jouke-Jan, Sinisalo Juha, Niiranen Teemu, Walsh Roddy, Schmidt Amand F, Choi Seung Hoan, Chang Kyong-Mi, Tsao Philip S, Matthews Paul M, Ware James S, Lumbers R Thomas, van der Crabben Saskia, Laukkanen Jari, Palotie Aarno, Amin Ahmad S, Charron Philippe, Meder Benjamin, Ellinor Patrick T, Daly Mark, Aragam Krishna G, Bezzina Connie R

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Аннотация

Dilated cardiomyopathy (DCM) is a heart muscle disease that represents an important cause of morbidity and mortality, yet causal mechanisms remain largely elusive. Here, we perform a large-scale genome-wide association study and multitrait analysis for DCM using 9,365 cases and 946,368 controls. We identify 70 genome-wide significant loci, which show broad replication in independent samples and map to 63 prioritized genes. Tissue, cell type and pathway enrichment analyses highlight the central role of the cardiomyocyte and contractile apparatus in DCM pathogenesis. Polygenic risk scores constructed from our genome-wide association study predict DCM across different ancestry groups, show differing contributions to DCM depending on rare pathogenic variant status and associate with systolic heart failure across various clinical settings. Mendelian randomization analyses reveal actionable potential causes of DCM, including higher bodyweight and higher systolic blood pressure. Our findings provide insights into the genetic architecture and mechanisms underlying DCM and myocardial function more broadly.

Для цитирования: Jurgens Sean J, Rämö Joel T, Kramarenko Daria R, Wijdeveld Leonoor F J M, Haas Jan, Chaffin Mark D, Garnier Sophie, Gaziano Liam, Weng Lu-Chen, Lipov Alex, Zheng Sean L, Henry Albert, Huffman Jennifer E, Challa Saketh, Rühle Frank, Verdugo Carmen Diaz, Krijger Juárez Christian, Kany Shinwan, van Orsouw Constance A, Biddinger Kiran, Poel Edwin, Elliott Amanda L, Wang Xin, Francis Catherine, Ruan Richard, Koyama Satoshi, Beekman Leander, Zimmerman Dominic S, Deleuze Jean-François, Villard Eric, Trégouët David-Alexandre, Isnard Richard, FinnGen, VA Million Veteran Program, HERMES Consortium, Boomsma Dorret I, de Geus Eco J C, Tadros Rafik, Pinto Yigal M, Wilde Arthur A M, Hottenga Jouke-Jan, Sinisalo Juha, Niiranen Teemu, Walsh Roddy, Schmidt Amand F, Choi Seung Hoan, Chang Kyong-Mi, Tsao Philip S, Matthews Paul M, Ware James S, Lumbers R Thomas, van der Crabben Saskia, Laukkanen Jari, Palotie Aarno, Amin Ahmad S, Charron Philippe, Meder Benjamin, Ellinor Patrick T, Daly Mark, Aragam Krishna G, Bezzina Connie R. Genome-wide association study reveals mechanisms underlying dilated cardiomyopathy and myocardial resilience.. Nature genetics. 2024. DOI: 10.1038/s41588-024-01975-5.

Предметные рубрики MeSH

Cardiomyopathy, DilatedGenome-Wide Association StudyHumansGenetic Predisposition to DiseaseMultifactorial InheritancePolymorphism, Single NucleotideMaleMyocardiumFemaleMyocytes, CardiacCase-Control StudiesMendelian Randomization Analysis
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