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Record W4404595279 · doi:10.1038/s41588-024-01952-y

Genome-wide association analysis provides insights into the molecular etiology of dilated cardiomyopathy

2024· article· en· W4404595279 on OpenAlexaff
Sean L. Zheng, Albert Henry, Douglas Cannie, Michael Lee, D.J. Miller, Kathryn A. McGurk, Isabelle Bond, Xiao Yun Xu, Hanane Issa, Catherine Francis, Antonio de Marvao, Pantazis Theotokis, Rachel Buchan, Doug Speed, Erik Abner, Lance Adams, Krishna G. Aragam, Johan Ärnlöv, Anna Axelsson Raja, Joshua Backman, John Baksi, Paul J.R. Barton, Kiran J. Biddinger, Eric Boersma, Jeffrey Brandimarto, Søren Brunak, Henning Bundgaard, David J. Carey, Philippe Charron, James P. Cook, Stuart A. Cook, Spiros Denaxas, Jean‐François Deleuze, Alex S. F. Doney, Perry Elliott, Christian Erikstrup, Tõnu Esko, Eric Farber‐Eger, Chris Finan, Sophie Garnier, Jonas Ghouse, Vilmantas Giedraitis, Daníel F. Guðbjartsson, Christopher M. Haggerty, Brian P. Halliday, Anna Helgadóttir, Harry Hemingway, Hans L. Hillege, Isabella Kardys, Lars Lind, Cecilia M. Lindgren, Brandon D. Lowery, Charlotte Manisty, Kenneth B. Margulies, James Moon, Ify Mordi, Michael P. Morley, Andrew D. Morris, Andrew P. Morris, Lori Morton, Mahdad Noursadeghi, Sisse Rye Ostrowski, Anjali Owens, Sanjay Prasad, Akshay Shekhar, Diane T. Smelser, Sundararajan Srinivasan, Kāri Stefánsson, Garðar Sveinbjörnsson, Petros Syrris, Mari‐Liis Tammesoo, Upasana Tayal, Maris Teder‐Laving, Unnur Thorsteinsdottir, Vinicius Tragante, David‐Alexandre Trégouët, Thomas A. Treibel, Henrik Ullum, Ana M. Valdes, Marion van Vugt, Abirami Veluchamy, W. M. Monique Verschuren, Eric Villard, Yifan Yang, Folkert W. Asselbergs, Marie‐Pierre Dubé, Patrick T. Ellinor, Chim C. Lang, Nilesh J. Samani, Svati H. Shah, J. G. Smith, Sundarajan Srinivasan, Ramachandran S. Vasan, W. M. Monique Verschuuren, Quinn S. Wells, Thomas P. Cappola, Aroon D. Hingorani, Declan P. O’Regan, Hilma Hólm, Michela Noseda, James S. Ware, R Thomas Lumbers

Bibliographic record

VenueNature Genetics · 2024
Typearticle
Languageen
FieldBiochemistry, Genetics and Molecular Biology
TopicRNA modifications and cancer
Canadian institutionsUniversité de MontréalMontreal Heart Institute
FundersMedical Research CouncilUniversity College LondonImperial College LondonRosetrees TrustDepartment of Health and Social CareNational Institute for Health and Care ResearchWellcome TrustBritish Heart FoundationCancer Research UKNovo Nordisk FondenIsrael Cancer Research Fund
KeywordsDilated cardiomyopathyBiologyPenetranceGeneticsGenome-wide association studyBiobankCardiomyopathyGenetic associationMultifactorial InheritancePopulationHeart failureEtiologyBioinformaticsComputational biologyGeneSingle-nucleotide polymorphismInternal medicineMedicinePhenotypeGenotype

Abstract

fetched live from OpenAlex

Dilated cardiomyopathy (DCM) is a leading cause of heart failure and cardiac transplantation. We report a genome-wide association study and multi-trait analysis of DCM (14,256 cases) and three left ventricular traits (36,203 UK Biobank participants). We identified 80 genomic risk loci and prioritized 62 putative effector genes, including several with rare variant DCM associations (MAP3K7, NEDD4L and SSPN). Using single-nucleus transcriptomics, we identify cellular states, biological pathways, and intracellular communications that drive pathogenesis. We demonstrate that polygenic scores predict DCM in the general population and modify penetrance in carriers of rare DCM variants. Our findings may inform the design of genetic testing strategies that incorporate polygenic background. They also provide insights into the molecular etiology of DCM that may facilitate the development of targeted therapeutics.

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)0.000
metaresearch head score (Gemma)0.000
Version: codex-gemma-dda1882f352aValidation status: machine_predicted_unvalidated
Candidate categoriesnone
Consensus categoriesnone
DomainCandidate signal: none · Consensus signal: none
Study designCandidate signal: Bench or experimental · Consensus signal: none
GenreCandidate signal: Empirical · Consensus signal: Empirical
Teacher disagreement score0.642
Threshold uncertainty score0.359

Codex and Gemma teacher scores by category

CategoryCodexGemma
Metaresearch0.0000.000
Meta-epidemiology (narrow)0.0000.000
Meta-epidemiology (broad)0.0000.000
Bibliometrics0.0000.001
Science and technology studies0.0000.000
Scholarly communication0.0000.000
Open science0.0000.000
Research integrity0.0000.000
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 head0.004
GPT teacher head0.240
Teacher spread0.236 · 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 designBench or experimental
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

Citations53
Published2024
Admission routes1
Has abstractyes

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