← Back to cohort
A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids
Shweta Ramdas, Jonathan Judd, Sarah E. Graham, Stavroula Kanoni, Yuxuan Wang, Ida Surakka, Brandon M. Wenz, Shoa L. Clarke, Alessandra Chesi, Andrew D. Wells, Konain Fatima Bhatti, Sailaja Vedantam, Thomas W. Winkler, Adam E. Locke, Eirini Marouli, Greg J.M. Zajac, Kuan-Han Wu, Ιωάννα Ντάλλα, Qin Hui, Derek Klarin, Austin T. Hilliard, Zeyuan Wang, Chao Xue, Guðmar Þorleifsson, Anna Helgadóttir, Daníel F. Guðbjartsson, Hilma Hólm, Ísleifur Ólafsson, Mi Yeong Hwang, Sohee Han, Masato Akiyama, Saori Sakaue, Chikashi Terao, Masahiro Kanai, Wei Zhou, Ben Brumpton, Humaira Rasheed, Aki S. Havulinna, Yogasudha Veturi, Jennifer A. Pacheco, Elisabeth A. Rosenthal, Todd Lingren, QiPing Feng, Iftikhar J. Kullo, Akira Narita, Jun Takayama, Hilary C. Martin, Karen A. Hunt, Bhavi Trivedi, Jeffrey Haessler, Franco Giulianini, Yuki Bradford, Jason E. Miller, Archie Campbell, Kuang Lin, Iona Y. Millwood, Asif Rasheed, George Hindy, Jessica D. Faul, Wei Zhao, David R. Weir, Constance Turman, Hongyan Huang, Mariaelisa Graff, Ananyo Choudhury, Dhriti Sengupta, Anubha Mahajan, Michael R. Brown, Weihua Zhang, Ketian Yu, Ellen M. Schmidt, Anita Pandit, Stefan Gustafsson, Xianyong Yin, Jian’an Luan, Jinghua Zhao, Fumihiko Matsuda, Hye-Mi Jang, Kyungheon Yoon, Carolina Medina‐Gómez, Achilleas Pitsillides, Andrew R. Wood, Yingji Ji, Zishan Gao, Simon Haworth, Ruth E. Mitchell, Jin Fang Chai, Mette Aadahl, Anne Ahrendt Bjerregaard, Jie Yao, Ani Manichaikul, Wen-Jane, Ann Chao, Helen R. Warren, Julia Ramírez, Jette Bork‐Jensen, Line Lund Kårhus, Anuj Goel, Maria Sabater‐Lleal, Raymond Noordam, Mauro Pala, Matteo Floris, Aaron F. McDaid, Pedro Marques‐Vidal, Matthias Wielscher, Stella Trompet, Naveed Sattar, Line T. Møllehave, Matthias Munz, Lingyao Zeng, Jianfeng Huang, Bin Yang, Alaitz Poveda, Azra Kurbasic, Sebastian Schönherr, Lukas Forer, Markus Scholz, Tessel E. Galesloot, Jonathan P. Bradfield, Sanni Ruotsalainen, E. Warwick Daw, Joseph M. Zmuda, Jonathan S. Mitchell, Christian Fuchsberger, Henry Christensen, Jennifer A. Brody, Phuong Le, Mary F. Feitosa, Mary K. Wojczynski, Daiane Hemerich, Michael Preuß, Massimo Mangino, Paraskevi Christofidou, Niek Verweij, Jan Walter Benjamins, Jorgen Engmann, Tsao L. Noah, Anurag Verma, Roderick C. Slieker, Ken Sin Lo, Nuno R. Zilhäo, Marcus E. Kleber, Graciela E. Delgado, Shaofeng Huo, Daisuke D. Ikeda, Hiroyuki Iha, Jian Yang, Jun Liu, Ayşe Demirkan, Hampton L. Leonard, Jonathan Marten, Carina Emmel, Börge Schmidt, Laura J. Smyth, Marisa Cañadas‐Garre, Chaolong Wang, Masahiro Nakatochi, Andrew Wong, Nina Hutri‐Kähönen, Xueling Sim, Rui Xia, Alicia Huerta‐Chagoya, Juan Carlos Fernández-López, Valeriya Lyssenko, Suraj S. Nongmaithem, Alagu Sankareswaran, Marguerite R. Irvin, Christopher Oldmeadow, Han‐Na Kim, Seungho Ryu, Paul R. H. J. Timmers, Liubov Arbeeva, Rajkumar Dorajoo, Leslie A. Lange, Gauri Prasad, Laura Lorés‐Motta, Marc Pauper, Jirong Long, Xiaohui Li, Elizabeth Theusch, Fumihiko Takeuchi, Cassandra N. Spracklen, Anu Loukola, Sailalitha Bollepalli, Sophie C. Warner, Ya Xing Wang, Wen Bin Wei, Teresa Nutile, Daniela Ruggiero, Shufeng Chen, Fangchao Liu, Jingyun Yang, Katherine A. Kentistou, Bernhard Banas, Anna Morgan, Karina Meidtner, Lawrence F. Bielak, Jennifer A. Smith, Prashantha Hebbar, Aliki‐Eleni Farmaki, Edith Hofer, Maoxuan Lin, Maria Pina Concas, Simona Vaccargiu, Peter J. van der Most, Niina Pitkänen, Brian E. Cade, Sander W. van der Laan, Kumaraswamy Naidu Chitrala, Stefan Weiß, Amy R. Bentley, Ayo P. Doumatey, Adebowale Adeyemo, Jong‐Young Lee, Eva RB Petersen, Aneta Aleksandra Nielsen, Hyeok Sun Choi, Maria Nethander, Sandra Freitag‐Wolf, Lorraine Southam, Nigel W. Rayner, Carol A. Wang, Shih-Yi Lin, Jun‐Sing Wang, Christian Couture, Leo‐Pekka Lyytikäinen, Kjell Nikus, Gabriel Cuéllar-Partida, Henrik Vestergaard, Bertha Hidalgo, Olga Giannakopoulou, Qiuyin Cai, Morgan O. Obura, Jessica van Setten, Karen He, Hua Tang, Natalie Terzikhan, Jae Hun Shin, Rebecca D. Jackson, Alex P. Reiner, Lisa W. Martin, Zhengming Chen, Liming Li, Takahisa Kawaguchi, Joachim Thiery, Lenore J. Launer, Huaixing Li, Mike A. Nalls, Olli T. Raitakari, Sahoko Ichihara, Sarah H. Wild, Christopher P. Nelson, Harry Campbell, Susanne Jäger, Toru Nabika, Fahd Al‐Mulla, Harri Niinikoski, Peter S. Braund, Ivana Kolčić, Péter Kovács, Tota Giardoglou, Tomohiro Katsuya, Dominique P.V. de Kleijn, Gert J. de Borst, Eung Kweon Kim, Hieab H.H. Adams, M. Arfan Ikram, Xiaofeng Zhu, Folkert W. Asselbergs, Adriaan O. Kraaijeveld, Joline W. J. Beulens, Xiao‐Ou Shu, Lοukianos S. Rallidis, Oluf Pedersen, Torben Hansen, Paul Mitchell, Alex W. Hewitt, Mika Kähönen, Louis Përusse, Claude Bouchard, Anke Tönjes, Yii‐Der Ida Chen, Craig E. Pennell, Trevor A. Mori, Wolfgang Lieb, André Franke, Claes Ohlsson, Dan Mellström, Yoon Shin Cho, Hyejin Lee, Jian‐Min Yuan, Woon‐Puay Koh, Sang Youl Rhee, Jeong‐Taek Woo, Iris M. Heid, Klaus Stark, Martina E. Zimmermann, Henry Völzke, Georg Homuth, Michele K. Evans, Alan B. Zonderman, Ozren Polašek, Gerard Pasterkamp, Imo E. Hoefer, Susan Redline, Katja Pahkala, Albertine J. Oldehinkel, Harold Snieder, Ginevra Biino, Reinhold Schmidt, Helena Schmidt, Stefania Bandinelli, George Dedoussis, Thangavel Alphonse Thanaraj, Patricia A. Peyser, Norihiro Kato, Matthias B. Schulze, Giorgia Girotto, Carsten A. Böger, Bettina Jung, Peter K. Joshi, David A. Bennett, Philip L. De Jager, Xiangfeng Lu, Vasiliki Mamakou, Mark J. Caulfield, Patricia B. Munroe, Xiuqing Guo, Marina Ciullo, Jost B. Jonas, Nilesh J. Samani, Jaakko Kaprio, Päivi Pajukanta, Teresa Tusié‐Luna, Carlos A. Aguilar‐Salinas, Linda S. Adair, Sonny Augustin Bechayda, H. Janaka de Silva, Ananda R. Wickremasinghe, Ronald M. Krauss, Jer‐Yuarn Wu, Wei Zheng, Anneke I. den Hollander, Dwaipayan Bharadwaj, Adolfo Correa, James G. Wilson, Lars Lind, Chew‐Kiat Heng, Amanda E. Nelson, Yvonne M. Golightly, James F. Wilson, Brenda W.J.H. Penninx, Hyung‐Lae Kim, John Attia, Rodney J. Scott, D. C. Rao, Donna K. Arnett, Mark Walker, Laura J. Scott, Heikki A. Koistinen, Giriraj R. Chandak, Josep M. Mercader, Clicerio González Villalpando, Lorena Orozco, Myriam Fornage, E Shyong Tai, Rob M. van Dam, Terho Lehtimäki, Nish Chaturvedi, Mitsuhiro Yokota, Jianjun Liu, Dermot F. Reilly, Amy Jayne McKnight, Frank Kee, Karl‐Heinz Jöckel, Mark I. McCarthy, Véronique Vitart, Caroline Hayward, Eleanor M. Simonsick, Cornelia M. van Duijn, Zi‐Bing Jin, Fan Lü, Haretsugu Hishigaki, Lin Xu, Winfried März, Vilmundur Guðnason, Jean‐Claude Tardif, Guillaume Lettre, Leen M. ‘t Hart, Petra J. M. Elders, Daniel J. Rader, Scott M. Damrauer, Meena Kumari, Mika Kivimäki, Pim van der Harst, Tim D. Spector, Ruth J. F. Loos, Michael A. Province, Esteban J. Parra, Miguel Cruz, Bruce M. Psaty, Ivan Brandslund, Peter P. Pramstaller, Charles N. Rotimi, Kaare Christensen, Samuli Ripatti, Elisabeth Widén, Håkon Håkonarson, Struan F.A. Grant, Lambertus A. Kiemeney, Jacqueline de Graaf, Markus Loeffler, Florian Kronenberg, Dongfeng Gu, Jeanette Erdmann, Heribert Schunkert, Paul W. Franks, Allan Linneberg, J. Wouter Jukema, Amit V. Khera, Minna Männikkö, Marjo‐Riitta Järvelin, Zoltán Kutalik, Cucca Francesco, Dennis O. Mook‐Kanamori, Ko Willems van Dijk, Hugh Watkins, David P. Strachan, Niels Grarup, Peter Sever, Neil R Poulter, Wayne Huey‐Herng Sheu, Jerome I. Rotter, Thomas Meinertz Dantoft, Fredrik Karpe, Matt J. Neville, Nicholas J. Timpson, Ching‐Yu Cheng, Tien Yin Wong, Chiea Chuen Khor, Hengtong Li, Charumathi Sabanayagam, Annette Peters, Christian Gieger, Andrew T. Hattersley, Nancy L. Pedersen, Patrik K. E. Magnusson, Dorret I. Boomsma, Eco J. C. de Geus, L. Adrienne Cupples, Joyce B. J. van Meurs, Mohsen Ghanbari, Penny Gordon‐Larsen, Wei Huang, Young Jin Kim, Yasuharu Tabara, Nicholas J. Wareham, Claudia Langenberg, Eleftheria Zeggini, Jaakko Tuomilehto, Johanna Kuusisto, Markku Laakso, Erik Ingelsson, Gonçalo R. Abecasis, John C. Chambers, Jaspal S. Kooner, Paul S. de Vries, Alanna C. Morrison, Scott Hazelhurst, Michèle Ramsay, Kari E. North, Martha L. Daviglus, Peter Kraft, Nicholas G. Martin, John B. Whitfield, Shahid Abbas, Danish Saleheen, Robin Walters, Michael V. Holmes, Corri Black, Blair H. Smith, Aris Baras, Anne E. Justice, Julie E. Buring, Paul M. Ridker, Daniel I. Chasman, Charles Kooperberg, Gen Tamiya, Masayuki Yamamoto, David A. van Heel, Richard C. Trembath, Wei‐Qi Wei, Gail P. Jarvik, Bahram Namjou, M. Geoffrey Hayes, Marylyn D. Ritchie, Pekka Jousilahti, Veikko Salomaa, Kristian Hveem, Bjørn Olav Åsvold, Michiaki Kubo, Yukinori Okada, Yoshinori Murakami, Bong-Jo Kim, Unnur Þorsteinsdóttir, Kāri Stefánsson, Jifeng Zhang, Y Eugene Chen, Yuk‐Lam Ho, Julie A. Lynch, Philip S. Tsao, Kyong‐Mi Chang, Kelly Cho, Christopher J. O’Donnell, John Michael Gaziano, Peter W.F. Wilson, Karen L. Mohlke, Timothy M. Frayling, Joel N. Hirschhorn, Sekar Kathiresan, Michael Boehnke, Pradeep Natarajan, Yan V. Sun, Andrew P. Morris, Panos Deloukas, Gina M. Peloso, Themistocles L. Assimes, Cristen J. Willer, Xiang Zhu, Christopher D. Brown
Bibliographic record
VenuebioRxiv (Cold Spring Harbor Laboratory) · 2021
Typepreprint
Languageen
FieldBiochemistry, Genetics and Molecular Biology
TopicGenetic Associations and Epidemiology
Canadian institutionsCentre for Global Health ResearchUniversité de MontréalUniversité LavalMontreal Heart InstituteUniversity of Toronto
FundersJohnson and JohnsonNovo Nordisk FondenSydäntutkimussäätiöNovo NordiskGovernment of the United KingdomWellcome TrustFinska LäkaresällskapetHelsingin YliopistoFoundation for Cardiovascular ResearchYale UniversityNational Heart, Lung, and Blood InstitutePfizerAmgenEli Lilly and CompanyEuropean CommissionSanofiHelsinki Institute of Life Science, Helsingin YliopistoAmerican Heart AssociationAmerican Diabetes Association
KeywordsGenome-wide association studyExpression quantitative trait lociBiologyQuantitative trait locusChromatinComputational biologyGeneticsGenePhenotypeLocus (genetics)Transcription factorCandidate geneGenetic associationSingle-nucleotide polymorphismGenotype
Abstract
Abstract A major challenge of genome-wide association studies (GWAS) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations, and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels, and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. Two prioritized genes, CREBRF and RRBP1 , show convergent evidence across functional datasets supporting their roles in lipid biology.
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 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: Empirical · Consensus signal: none
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) | 0.001 | 0.001 |
| Bibliometrics | 0.003 | 0.002 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.000 | 0.001 |
| 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 head0.026
GPT teacher head0.246
Teacher spread0.220 · 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
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
Citations4
Published2021
Admission routes1
Has abstractyes