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Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution
Anne E. Justice, Tugce Karaderi, Heather M. Highland, Kristin L. Young, Mariaelisa Graff, Yingchang Lu, Valérie Turcot, Paul L. Auer, Rebecca S. Fine, Xiuqing Guo, Claudia Schurmann, Adelheid Lempradl, Eirini Marouli, Anubha Mahajan, Adam E. Locke, Carolina Medina‐Gómez, Tõnu Esko, Sailaja Vedantam, Ayush Giri, Ken Sin Lo, Tamuno Alfred, Poorva Mudgal, Maggie C. Y. Ng, Nancy L. Heard‐Costa, Mary F. Feitosa, Alisa K. Manning, Sara M. Willems, Suthesh Sivapalaratnam, Gonçalo R. Abecasis, Dewan S Alam, Matthew Allison, Philippe Amouyel, Zorayr Arzumanyan, Beverley Balkau, Lisa Bastarache, Sven Bergmann, Lawrence F. Bielak, Matthias Blüher, Michael Boehnke, Heiner Boeing, Eric Boerwinkle, Carsten A. Böger, Jette Bork‐Jensen, Erwin P. Böttinger, Donald W. Bowden, Ivan Brandslund, Linda Broer, Amber Burt, Adam S. Butterworth, Mark J. Caulfield, Giancarlo Cesana, John C. Chambers, Daniel I. Chasman, Yii‐Der Ida Chen, Rajiv Chowdhury, Cramer Christensen, Audrey Y. Chu, Francis S. Collins, James P. Cook, Amanda J. Cox, David S. Crosslin, John Danesh, Paul I. W. de Bakker, Simon de Denus, Renée de Mutsert, George Dedoussis, Ellen W. Demerath, Joe Dennis, Joshua C. Denny, Emanuele Di Angelantonio, Marcus Dörr, Fotios Drenos, Marie‐Pierre Dubé, Alison M. Dunning, Douglas F. Easton, Paul Elliott, Εvangelos Εvangelou, Aliki‐Eleni Farmaki, Shuang Feng, Ele Ferrannini, Jean Ferrières, José C. Florez, Myriam Fornage, Caroline S. Fox, Paul W. Franks, Nele Friedrich, Wei Gan, Ilaria Gandin, Paolo Gasparini, Vilmantas Giedraitis, Giorgia Girotto, Mathias Gorski, Harald Grallert, Niels Grarup, Megan L. Grove, Stefan Gustafsson, Jeff Haessler, Torben Hansen, Andrew T. Hattersley, Caroline Hayward, Iris M. Heid, Oddgeir L. Holmen, G. Kees Hovingh, Joanna M. M. Howson, Yao Hu, Yi‐Jen Hung, Kristian Hveem, M. Arfan Ikram, Erik Ingelsson, Anne Jackson, Gail P. Jarvik, Yucheng Jia, Torben Jørgensen, Johanne Marie Justesen, Bratati Kahali, Maria Karaleftheri, Sharon Kardia, Fredrik Karpe, Frank Kee, Hidetoshi Kitajima, Pirjo Komulainen, Jaspal S. Kooner, Péter Kovács, Bernhard K. Krämer, Kari Kuulasmaa, Johanna Kuusisto, Markku Laakso, Timo A. Lakka, David Lamparter, Leslie A. Lange, Claudia Langenberg, Eric B. Larson, Nanette R. Lee, Wen‐Jane Lee, Terho Lehtimäki, Cora E. Lewis, Huaixing Li, Jin Li, Ruifang Li‐Gao, Li‐An Lin, Lin Xu, Lars Lind, Jaana Lindström, Allan Linneberg, Ching‐Ti Liu, Dajiang J. Liu, Jian’an Luan, Leo‐Pekka Lyytikäinen, Stuart MacGregor, Reedik Mägi, Satu Männistö, Gaëlle Marenne, Jonathan Marten, Nicholas G. D. Masca, Mark I. McCarthy, Karina Meidtner, Evelin Mihailov, Leena Moilanen, Marie Moitry, Dennis O. Mook‐Kanamori, Anna Morgan, Andrew P. Morris, Martina Müller‐Nurasyid, Patricia B. Munroe, Narisu Narisu, Christopher P. Nelson, Matt J. Neville, Ioanna Ntalla, Jeffrey R. O’Connell, Katharine R. Owen, Oluf Pedersen, Gina M. Peloso, Craig E. Pennell, Markus Perola, James A. Perry, John R. B. Perry, Tune H. Pers, Ailith Ewing, Ozren Polašek, Olli T. Raitakari, Asif Rasheed, Chelsea K. Raulerson, Rainer Rauramaa, Dermot F. Reilly, Alex P. Reiner, Paul M. Ridker, Manuel A. Rivas, Neil Robertson, Antonietta Robino, Igor Rudan, Katherine S. Ruth, Danish Saleheen, Veikko Salomaa, Pamela J. Schreiner, Matthias B. Schulze, Robert A. Scott, Marcelo P. Segura-Lepe, Xueling Sim, Andrew Slater, Kerrin S. Small, Blair H. Smith, Jennifer A. Smith, Lorraine Southam, Timothy D. Spector, Elizabeth K. Speliotes, Kāri Stefánsson, Valgerður Steinthórsdóttir, Kathleen Stirrups, Konstantin Strauch, Heather M. Stringham, Michael Stümvoll, Liang Sun, Praveen Surendran, Karin M. A. Swart, Jean‐Claude Tardif, Kent D. Taylor, Alexander Teumer, Deborah J. Thompson, Guðmar Þorleifsson, Unnur Þorsteinsdóttir, Betina H. Thuesen, Anke Tönjes, Mina Torres, Emmanouil Tsafantakis, Jaakko Tuomilehto, André G. Uitterlinden, Matti Uusitupa, Cornelia M. van Duijn, Mauno Vanhala, Rohit Varma, Sita H. Vermeulen, Henrik Vestergaard, Véronique Vitart, Thomas Vogt, Dragana Vuckovic, Lynne E. Wagenknecht, Mark Walker, Lars Wallentin, Feijie Wang, Carol A. Wang, Shuai Wang, Nicholas J. Wareham, Helen Warren, Dawn Waterworth, Jennifer Wessel, Harvey D. White, Cristen J. Willer, James G. Wilson, Andrew R. Wood, Ying Wu, Hanieh Yaghootkar, Jie Yao, Laura M. Yerges‐Armstrong, Robin Young, Eleftheria Zeggini, Xiaowei Zhan, Weihua Zhang, Wei Zhao, Zheng He, Wei Zhou, M. Carola Zillikens, Fernando Rivadeneira, Ingrid B. Borecki, J. Andrew Pospisilik, Panos Deloukas, Timothy M. Frayling, Guillaume Lettre, Karen L. Mohlke, Jerome I. Rotter, Zoltán Kutalik, Joel N. Hirschhorn, L. Adrienne Cupples, Ruth J. F. Loos, Kari E. North, Cecilia M. Lindgren
Bibliographic record
VenueNature Genetics · 2019
Typereview
Languageen
FieldBiochemistry, Genetics and Molecular Biology
TopicGenetic Associations and Epidemiology
Canadian institutionsYork UniversityUniversité de MontréalMontreal Heart Institute
FundersFP7 Ideas: European Research CouncilEunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNational Center for Advancing Translational SciencesNational Institute of Diabetes and Digestive and Kidney DiseasesNational Institute of General Medical SciencesHelmholtz Zentrum MünchenNational Human Genome Research InstituteHrvatska Zaklada za ZnanostNational Institute on Drug AbuseImperial College Healthcare NHS TrustNIHR Oxford Biomedical Research CentreHjärt-LungfondenMedical Research CouncilScottish Funding CouncilNIHR Cambridge Biomedical Research CentreNIHR BioResourceUniversiteit LeidenNational Heart, Lung, and Blood InstituteKaiser Foundation Research InstituteDirectorate for Biological SciencesNational Institutes of HealthH. Lundbeck A/SFondation LeenaardsInstitut de Cardiologie de MontréalMarcus och Amalia Wallenbergs minnesfondGovernment of Western AustraliaPaavo Nurmen SäätiöTampereen TuberkuloosisäätiöNational Health and Medical Research CouncilDeutsche KrebshilfeSydäntutkimussäätiöVetenskapsrådetNovo NordiskNational Institute for Health Research Health Protection Research UnitUniversitätsklinikum RegensburgDiabetesliittoLeids Universitair Medisch CentrumSteno Diabetes Center CopenhagenSystemsX.chUniversitetet i BergenEmil Aaltosen SäätiöWake Forest School of MedicineTaichung Veterans General HospitalHelse VestNational Cancer InstituteEuropean Regional Development FundMax-Planck-GesellschaftRegion HovedstadenKuopion Yliopistollinen SairaalaAmerican Heart AssociationSuomen KulttuurirahastoTurun Yliopistollinen KeskussairaalaEuropean CommissionKnut och Alice Wallenbergs StiftelseTekesSchweizerischer Nationalfonds zur Förderung der Wissenschaftlichen ForschungNational Medical Research CouncilNorges ForskningsrådAustralian GovernmentQIMR Berghofer Medical Research InstituteLunds UniversitetDeutsche ForschungsgemeinschaftNederlandse Organisatie voor Wetenschappelijk OnderzoekMinistero della SaluteEesti TeadusagentuurPäivikki ja Sakari Sohlbergin SäätiöRaine Medical Research FoundationPublic Health EnglandEdith Cowan UniversityDiabetestutkimussäätiöFoundation for Cardiovascular ResearchZonMwUniversité de MontréalKelaNational Natural Science Foundation of ChinaNational Science CouncilBritish Heart FoundationNational Institute for Health and Care ResearchJohns Hopkins UniversityWellcome TrustCancer Research UKRoyal Marsden NHS Foundation TrustSocialdepartementetSchool of Medicine, Boston UniversityEuropean Hematology AssociationLi Ka Shing FoundationUniversity of Notre DameImperial College LondonFondation Institut de Cardiologie de MontréalNIHR Exeter Clinical Research FacilityErasmus Medisch CentrumLundbeckfondenDoktor Robert Pfleger-StiftungNational Science FoundationFondation LeducqDiabetesforbundetPfizerNorthwestern UniversityHorizon 2020 Framework ProgrammeUniversity of MinnesotaJuho Vainion SäätiöNovo Nordisk Fonden
KeywordsBiologyGenome-wide association studyGeneticsGeneBody fat distributionMinor allele frequencyAdipose tissueAlleleAllele frequencyEndocrinologySingle-nucleotide polymorphismGenotype
Abstract
Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
metaresearch head score (Codex)0.001
metaresearch head score (Gemma)0.002
Version: metacan-v3-hybrid-931329e0061cValidation status: machine_predicted_unvalidated
Candidate categoriesnone
Consensus categoriesnone
DomainCandidate signal: none · Consensus signal: none
Study designCandidate signal: Observational · Consensus signal: none
GenreCandidate signal: Review · Consensus signal: Review
Teacher disagreement score0.003
Threshold uncertainty score0.010
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.002 | 0.002 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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 head0.023
GPT teacher head0.327
Teacher spread0.304 · how far apart the two teachers sit on this one work
Validation status
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
The models applied no category: nothing in the taxonomy fit this work.
Study designObservational
Domainnot available
GenreReview
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".
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Citations112
Published2019
Admission routes2
Has abstractno