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Record W4404595278 · doi:10.1038/s41588-024-01975-5

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

2024· article· en· W4404595278 on OpenAlexaff
Sean J. Jurgens, Joel Rämö, Daria R. Kramarenko, Leonoor F. J. M. Wijdeveld, Jan Haas, Mark Chaffin, Sophie Garnier, Liam Gaziano, Lu‐Chen Weng, Alex Lipov, Sean L. Zheng, Albert Henry, Jennifer E. Huffman, Saketh Challa, Frank Rühle, Carmen Diaz Verdugo, Christian Krijger Juárez, Shinwan Kany, Constance A. van Orsouw, Kiran J. Biddinger, Edwin Poel, Amanda L. Elliott, Xin Wang, Catherine Francis, Richard Ruan, Satoshi Koyama, Leander Beekman, Dominic S. Zimmerman, Jean‐François Deleuze, Eric Villard, David‐Alexandre Trégouët, Richard Isnard, D.I. Boomsma, Eco J. C. de Geus, Rafik Tadros, Yigal M. Pinto, Arthur A.M. Wilde, Jouke‐Jan Hottenga, Juha Sinisalo, Teemu Niiranen, Roddy Walsh, Amand F. Schmidt, Seung Hoan Choi, Kyong‐Mi Chang, Philip S. Tsao, Paul M. Matthews, James S. Ware, R Thomas Lumbers, Saskia van der Crabben, Jari A. Laukkanen, Aarno Palotie, Ahmad S. Amin, Philippe Charron, Benjamin Meder, Patrick T. Ellinor, Mark J. Daly, Krishna G. Aragam, Connie R. Bezzina

Bibliographic record

VenueNature Genetics · 2024
Typearticle
Languageen
FieldBiochemistry, Genetics and Molecular Biology
TopicGenetic Associations and Epidemiology
Canadian institutionsUniversité de MontréalMontreal Heart Institute
FundersHORIZON EUROPE European Innovation CouncilNational Heart, Lung, and Blood InstituteNational Institutes of HealthAssociação Fundo de Incentivo à PesquisaAgence Nationale de la RechercheDeutsche ForschungsgemeinschaftEuropean CommissionSir Jules Thorn Charitable TrustBritish Heart FoundationFoundation for the National Institutes of HealthAmsterdam University Medical CentersHartstichtingAmerican Heart AssociationU.S. Department of Veterans AffairsZonMwAarne Koskelon Säätiö
KeywordsMendelian randomizationGenome-wide association studyBiologyDilated cardiomyopathyGenetic architectureHeart failureGenomeGenetic associationGeneticsDiseaseCardiomyopathyQuantitative trait locusGeneSingle-nucleotide polymorphismInternal medicineGenetic variantsMedicineGenotype

Abstract

fetched live from OpenAlex

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.

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.

How this classification was reachedexpand

Full frame distilled prediction

Teacher imitation

Not calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.

metaresearch head score (Codex)0.001
metaresearch head score (Gemma)0.001
Version: codex-gemma-dda1882f352aValidation status: machine_predicted_unvalidated
Candidate categoriesnone
Consensus categoriesnone
DomainCandidate signal: none · Consensus signal: none
Study designCandidate signal: Observational · Consensus signal: Observational
GenreCandidate signal: Empirical · Consensus signal: Empirical
Teacher disagreement score0.113
Threshold uncertainty score0.833

Codex and Gemma teacher scores by category

CategoryCodexGemma
Metaresearch0.0010.001
Meta-epidemiology (narrow)0.0000.000
Meta-epidemiology (broad)0.0000.000
Bibliometrics0.0000.000
Science and technology studies0.0000.000
Scholarly communication0.0000.000
Open science0.0000.000
Research integrity0.0010.000
Insufficient payload (model declined to judge)0.0000.000

Machine scores (provisional)

The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.

Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.

Opus teacher head0.011
GPT teacher head0.280
Teacher spread0.269 · how far apart the two teachers sit on this one work
Validation statusscore_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it

Classification

machine, unvalidated

Machine predicted; a candidate call from one teacher head, not a consensus.

The models applied no category: nothing in the taxonomy fit this work.
Study designObservational
Domainnot available
GenreEmpirical

How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".

Quick stats

Citations49
Published2024
Admission routes1
Has abstractyes

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