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Large-scale exome array summary statistics resources for glycemic traits to aid effector gene prioritization

2023· preprint· en· W4387823564 on OpenAlexaff
Sara M. Willems, Natasha Hui Jin Ng, Juan Fernandez, Rebecca S. Fine, Eleanor Wheeler, Jennifer Wessel, Hidetoshi Kitajima, Gaëlle Marenne, Xueling Sim, Hanieh Yaghootkar, Shuai Wang, Sai Chen, Yuning Chen, Yii‐Der Ida Chen, Niels Grarup, Ruifang Li‐Gao, Tibor V. Varga, Jennifer L. Asimit, Shuang Feng, Rona J. Strawbridge, Erica L. Kleinbrink, Tarunveer S. Ahluwalia, Ping An, Emil V. R. Appel, Dan E. Arking, Juha Auvinen, Lawrence F. Bielak, Nathan A. Bihlmeyer, Jette Bork‐Jensen, Jennifer A. Brody, Archie Campbell, Audrey Y. Chu, Gail Davies, Ayşe Demirkan, James S. Floyd, Franco Giulianini, Xiuqing Guo, Stefan Gustafsson, Anne Jackson, Jóhanna Jakobsdóttir, Marjo‐Riitta Järvelin, Richard A. Jensen, Stavroula Kanoni, Sirkka Keinänen‐Kiukaanniemi, Man Li, Yingchang Lu, Jian’an Luan, Alisa K. Manning, Jonathan Marten, Karina Meidtner, Dennis O. Mook‐Kanamori, Taulant Muka, Giorgio Pistis, Bram P. Prins, Kenneth Rice, Serena Sanna, Albert V. Smith, Jennifer A. Smith, Lorraine Southam, Heather M. Stringham, Vinicius Tragante, Sander W. van der Laan, Helen R. Warren, Jie Yao, Andrianos M. Yiorkas, Weihua Zhang, Wei Zhao, Mariaelisa Graff, Heather M. Highland, Anne E. Justice, Eirini Marouli, Carolina Medina‐Gómez, Saima Afaq, Wesam A. Alhejily, Najaf Amin, Folkert W. Asselbergs, Lori L. Bonnycastle, Michiel L. Bots, Ivan Brandslund, Ji Chen, John Danesh, Renée de Mutsert, Abbas Dehghan, Tapani Ebeling, Paul Elliott, Aliki‐Eleni Farmaki, Jessica D. Faul, Paul W. Franks, Steve Franks, Andreas Fritsche, Anette P. Gjesing, Mark O. Goodarzi, Vilmundur Guðnason, Göran Hallmans, Tamara B. Harris, Karl‐Heinz Herzig, Marie‐France Hivert, Torben Jørgensen, Marit E. Jørgensen, Pekka Jousilahti, Eero Kajantie, Maria Karaleftheri, Sharon L. R. Kardia, Leena Kinnunen, Heikki A. Koistinen, Pirjo Komulainen, Péter Kovács, Johanna Kuusisto, Markku Laakso, Leslie A. Lange, Lenore J. Launer, Aaron Leong, Jaana Lindström, Jocelyn E. Manning Fox, Satu Männistö, Nisa M. Maruthur, Leena Moilanen, Antonella Mulas, Mike A. Nalls, Matthew Neville, James S. Pankow, Alison Pattie, Annette Peters, Hannu Puolijoki, Asif Rasheed, Paul Redmond, Frida Renström, Michael Roden, Danish Saleheen, Juha Saltevo, Kai Savonen, Sylvain Sebért, Tea Skaaby, Kerrin S. Small, Alena Stančáková, Jakob Stokholm, Konstantin Strauch, E Shyong Tai, Kent D. Taylor, Betina H. Thuesen, Anke Tönjes, Emmanouil Tsafantakis, J Tuomilehto, Matti Uusitupa, Marja Vääräsmäki, Ilonca Vaartjes, Magdalena Żołędziewska, Gonçalo R. Abecasis, Beverley Balkau, Hans Bisgaard, Alexandra I. F. Blakemore, Matthias Blüher, Heiner Boeing, Eric Boerwinkle, Klaus Bønnelykke, Erwin P. Böttinger, Mark J. Caulfield, John C. Chambers, Daniel I. Chasman, Ching‐Yu Cheng, Francis S. Collins, Josef Coresh, Francesco Cucca, Gert J. de Borst, Ian J. Deary, George Dedoussis, Panos Deloukas, Hester M. den Ruijter, Josée Dupuis, Michele K. Evans, Ele Ferrannini, Oscar H. Franco, Harald Grallert, Torben Hansen, Andrew T. Hattersley, Caroline Hayward, Joel N. Hirschhorn, M. Arfan Ikram, Erik Ingelsson, Fredrik Karpe, Kay-Tee Kaw, Wieland Kieß, Jaspal S. Kooner, Antje Körner, Timo A. Lakka, Claudia Langenberg, Lars Lind, Cecilia M. Lindgren, Allan Linneberg, Leonard Lipovich, Ching‐Ti Liu, Jun Liu, Ruth J. F. Loos, Patrick E. MacDonald, Karen L. Mohlke, Andrew D. Morris, Patricia B. Munroe, Alison D. Murray, Sandosh Padmanabhan, Gerard Pasterkamp, Oluf Pedersen, Patricia A. Peyser, Ozren Polašek, David J. Porteous, Michael A. Province, Bruce M. Psaty, Rainer Rauramaa, Paul M. Ridker, Olov Rolandsson, Patrik Rorsman, Frits R. Rosendaal, Igor Rudan, Veikko Salomaa, Matthias B. Schulze, Robert Sladek, Blair H. Smith, Timothy D. Spector, John M. Starr, Michael Stümvoll, Cornelia M. van Duijn, Mark Walker, Nicholas J. Wareham, David R. Weir, James G. Wilson, Tien Yin Wong, Eleftheria Zeggini, Alan B. Zonderman, Jerome I. Rotter, Andrew P. Morris, Michael Boehnke, José C. Florez, Mark I. McCarthy, James B. Meigs, Anubha Mahajan, Robert A. Scott, Anna L. Gloyn, Inês Barroso

Bibliographic record

VenueWellcome Open Research · 2023
Typepreprint
Languageen
FieldBiochemistry, Genetics and Molecular Biology
TopicGenetic Associations and Epidemiology
Canadian institutionsUniversity of AlbertaMcGill University
FundersBiotechnology and Biological Sciences Research CouncilNational Heart, Lung, and Blood InstituteNational Institute of Mental HealthDanish Agency for Science and Higher EducationDirectorate for Biological SciencesNational Institutes of HealthWellcome TrustUniversität LeipzigNational Center on Minority Health and Health DisparitiesManpei Suzuki Diabetes FoundationOulun YliopistoMedical Research CouncilLeids Universitair Medisch CentrumAugustinus FondenDiabetesforeningenVetenskapsrådetZonMwUniversiteit LeidenEuropean CommissionNational Institute on Minority Health and Health DisparitiesNederlandse Organisatie voor Wetenschappelijk OnderzoekDeutsche ForschungsgemeinschaftRegion HovedstadenNovo NordiskRoyal SocietyAgency for Science, Technology and ResearchHelmholtz Zentrum MünchenAmerican Diabetes AssociationForsknings- og InnovationsstyrelsenRoyal Society of EdinburghAcademy of FinlandEuropean Regional Development FundNHLBI Division of Intramural ResearchNational Institute on AgingHelsefondenBundesministerium für Bildung und ForschungUniversity of EdinburghMassachusetts General HospitalCentre for Cognitive Ageing and Cognitive EpidemiologyBiocenter, University of OuluNational Institute for Health and Care ResearchHjerteforeningenAge UKNational Institute of Diabetes and Digestive and Kidney DiseasesTekesScottish GovernmentSundhed og Sygdom, Det Frie ForskningsrådWake Forest University
KeywordsPrioritizationExome sequencingEffectorScale (ratio)ExomeComputational biologyGlycemicStatisticsComputer scienceBiologyGeneGeneticsPhenotypeMathematicsGeographyBiotechnologyEngineeringInsulinImmunologyManagement scienceCartography

Abstract

fetched live from OpenAlex

Background: Genome-wide association studies for glycemic traits have identified hundreds of loci associated with these biomarkers of glucose homeostasis. Despite this success, the challenge remains to link variant associations to genes, and underlying biological pathways. Methods: To identify coding variant associations which may pinpoint effector genes at both novel and previously established genome-wide association loci, we performed meta-analyses of exome-array studies for four glycemic traits: glycated hemoglobin (HbA1c, up to 144,060 participants), fasting glucose (FG, up to 129,665 participants), fasting insulin (FI, up to 104,140) and 2hr glucose post-oral glucose challenge (2hGlu, up to 57,878). In addition, we performed network and pathway analyses. Results: Single-variant and gene-based association analyses identified coding variant associations at more than 60 genes, which when combined with other datasets may be useful to nominate effector genes. Network and pathway analyses identified pathways related to insulin secretion, zinc transport and fatty acid metabolism. HbA1c associations were strongly enriched in pathways related to blood cell biology. Conclusions: Our results provided novel glycemic trait associations and highlighted pathways implicated in glycemic regulation. Exome-array summary statistic results are being made available to the scientific community to enable further discoveries.

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)0.005
metaresearch head score (Gemma)0.002
Version: codex-gemma-dda1882f352aValidation status: machine_predicted_unvalidated
Candidate categoriesMeta-epidemiology (narrow)
Consensus categoriesnone
DomainCandidate signal: none · Consensus signal: none
Study designCandidate signal: Not applicable · Consensus signal: Not applicable
GenreCandidate signal: Empirical · Consensus signal: Empirical
Teacher disagreement score0.277
Threshold uncertainty score1.000

Codex and Gemma teacher scores by category

CategoryCodexGemma
Metaresearch0.0050.002
Meta-epidemiology (narrow)0.0000.000
Meta-epidemiology (broad)0.0010.000
Bibliometrics0.0000.000
Science and technology studies0.0000.000
Scholarly communication0.0000.000
Open science0.0020.003
Research integrity0.0010.001
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 head0.083
GPT teacher head0.395
Teacher spread0.311 · 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.

Study designNot applicable
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

Citations7
Published2023
Admission routes1
Has abstractyes

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