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Genome sequencing unveils a regulatory landscape of platelet reactivity
Ali R. Keramati, Ming‐Huei Chen, Benjamin A.T. Rodriguez, Lisa R. Yanek, Arunoday Bhan, Brady Gaynor, Kathleen A. Ryan, Jennifer A. Brody, Xue Zhong, Qiang Wei, Namiko Abe, Gonçalo R. Abecasis, François Aguet, Christine M. Albert, Laura Almasy, Alvaro Alonso, Seth A. Ament, Peter Anderson, Pramod Anugu, Deborah Applebaum‐Bowden, Kristin Ardlie, Dan E. Arking, Donna K. Arnett, Allison E. Ashley‐Koch, Stella Aslibekyan, Tim Assimes, Paul L. Auer, Dimitrios Avramopoulos, Najib Ayas, Adithya Balasubramanian, John Barnard, Kathleen C. Barnes, R. Graham Barr, Emily Barron‐Casella, Lucas Barwick, Terri Beaty, Gerald J. Beck, Diane M. Becker, Lewis C. Becker, Rebecca Beer, Amber L. Beitelshees, Emelia J. Benjamin, Takis Benos, Marcos Bezerra, Larry Bielak, Joshua C. Bis, Thomas W. Blackwell, John Blangero, Eric Boerwinkle, Donald W. Bowden, Russell Bowler, Ulrich Broeckel, Jai Broome, Deborah Brown, Karen Bunting, Esteban G. Burchard, Carlos D. Bustamante, Erin Buth, Brian E. Cade, Jonathan Cardwell, Vincent J. Carey, Julie Carrier, Cara L. Carty, Richard Casaburi, Juan P. Romero, James F. Casella, Peter J. Castaldi, Mark Chaffin, Christy Chang, Yi‐Cheng Chang, Daniel I. Chasman, Sameer Chavan, Bo-Juen Chen, Wei‐Min Chen, Y Eugene Chen, Michael Cho, Seung Hoan Choi, Lee‐Ming Chuang, Mina K. Chung, Ren‐Hua Chung, Clary B. Clish, Suzy Comhair, Matthew P. Conomos, Elaine Cornell, Adolfo Correa, Carolyn Crandall, James D. Crapo, L. Adrienne Cupples, Joanne E. Curran, Jeffrey L. Curtis, Brian Custer, Coleen Damcott, Dawood Darbar, Sean P. David, Colleen Davis, Michelle Daya, Mariza de Andrade, Lisa de las Fuentes, Paul S. de Vries, Michael R. DeBaun, Ranjan Deka, Dawn L. DeMeo, Scott E. Devine, Huyen Dinh, HarshaVardhan Doddapaneni, Qing Duan, Shannon Dugan‐Perez, Ravi Duggirala, Jon Peter Durda, Susan K. Dutcher, Charles B. Eaton, Lynette Ekunwe, Adel Boueiz, Patrick T. Ellinor, Leslie S. Emery, Serpil C. Erzurum, Charles R. Farber, Jesse Farek, Tasha E. Fingerlin, Matthew Flickinger, Myriam Fornage, Nora Franceschini, Chris Frazar, Mao Fu, Stephanie M. Fullerton, Lucinda Fulton, Stacey Gabriel, Weiniu Gan, Shanshan Gao, Yan Gao, Margery Gass, Heather Geiger, Bruce D. Gelb, Mark W. Geraci, Søren Germer, Robert E. Gerszten, Auyon Ghosh, Richard A. Gibbs, Chris Gignoux, Mark T. Gladwin, David C. Glahn, Stephanie M. Gogarten, Da‐Wei Gong, Harald H.H. Göring, Sharon Graw, Kathryn J. Gray, Daniel Grine, Colin Gross, C. Charles Gu, Yue Guan, Xiuqing Guo, Namrata Gupta, David M. Haas, Jeff Haessler, Michael E. Hall, Yi Han, Patrick J. Hanly, Daniel Harris, Nicola L. Hawley, Jiang He, Ben Heavner, Susan R. Heckbert, Ryan D. Hernandez, David Herrington, Craig P. Hersh, Bertha Hidalgo, James E. Hixson, Brian D. Hobbs, John E. Hokanson, Elliott Hong, Karin F. Hoth, Chao A. Hsiung, Taobo Hu, Yi‐Jen Hung, Haley Huston, Chii Min Hwu, Marguerite R. Irvin, Rebecca D. Jackson, Deepti Jain, Cashell E. Jaquish, Jill M. Johnsen, Andrew D. Johnson, Craig Johnson, Rich Johnston, Kimberly Marie Jones, Hyun Min Kang, Robert M. Kaplan, Sharon L. R. Kardia, Shannon Kelly, Eimear Kenny, Michael D. Kessler, Alyna Khan, Ziad Khan, Wonji Kim, John Kimoff, Gregory L. Kinney, Barbara A. Konkle, Charles Kooperberg, Holly Kramer, Christoph Lange, Ethan M. Lange, Leslie Lange, Cathy C. Laurie, Cecelia Laurie, Meryl S. LeBoff, Jiwon Lee, Sandra Lee, Wen‐Jane Lee, Jonathon LeFaive, David Levine, Daniel Levy, Joshua P. Lewis, Xiaohui Li, Yun Li, Henry J. Lin, Honghuang Lin, Xihong Lin, Simin Liu, Yongmei Liu, Yu Liu, Ruth J. F. Loos, Steven A. Lubitz, Kathryn L. Lunetta, James Luo, Ulysses J. Magalang, Michael C. Mahaney, Barry J. Make, Ani Manichaikul, Alisa K. Manning, JoAnn E. Manson, Lisa W. Martin, Melissa Marton, Susan Mathai, Rasika A. Mathias, Susanne May, Patrick F. McArdle, Merry‐Lynn McDonald, Sean McFarland, Stephen T. McGarvey, Daniel McGoldrick, Caitlin McHugh, Becky McNeil, Hao Mei, James B. Meigs, Vipin K. Menon, Luisa Mestroni, Ginger Metcalf, Deborah A. Meyers, Emmanuel Mignot, Julie Mikulla, Yuan‐I Min, Mollie Minear, Ryan L. Minster, Braxton D. Mitchell, Matt Moll, Zeineen Momin, May E. Montasser, Courtney G. Montgomery, Donna M. Muzny, Josyf C. Mychaleckyj, Girish N. Nadkarni, Rakhi P. Naik, Take Naseri, Pradeep Natarajan, Sergeï Nekhai, Sarah C. Nelson, Bonnie Neltner, Caitlin Nessner, Deborah A. Nickerson, Osuji Nkechinyere, Kari E. North, Jeff O’Connell, Tim O’Connor, Heather M. Ochs‐Balcom, Geoffrey Okwuonu, Allan I Pack, David T. Paik, James S. Pankow, George Papanicolaou, Gina M. Peloso, Juan M. Peralta, Marco Perez, James A. Perry, Patricia A. Peyser, Lawrence S. Phillips, Jacob Pleiness, Toni I. Pollin, Wendy S. Post, Julia Powers Becker, Meher Preethi Boorgula, Michael Preuß, Bruce M. Psaty, Pankaj Qasba, Dandi Qiao, Zhaohui Qin, Nicholas Rafaels, Laura M. Raffield, Mahitha Rajendran, Ramachandran S. Vasan, D. C. Rao, Laura J. Rasmussen‐Torvik, Aakrosh Ratan, Susan Redline, Robert M. Reed, Catherine Reeves, Elizabeth A. Regan, Alex P. Reiner, Muagututi‘a Sefuiva Reupena, Kenneth Rice, Stephen S. Rich, Rébecca Robillard, Nicolas Robine, Dan M. Roden, Carolina Roselli, Jerome I. Rotter, Ingo Ruczinski, Alexi Runnels, Pamela Russell, Sarah Ruuska, Éster Cerdeira Sabino, Danish Saleheen, Shabnam Salimi, Sejal Salvi, Steven L. Salzberg, Kevin Sandow, Vijay G. Sankaran, Jireh Santibanez, Karen Schwander, David C. Schwartz, Frank C. Sciurba, Christine Seidman, Jonathan G. Seidman, Frédéric Sériès, Vivien Sheehan, Stephanie L. Sherman, Amol C. Shetty, Aniket Shetty, Wayne Hui-Heng Sheu, M. Benjamin Shoemaker, Brian Silver, Edwin K. Silverman, Robert Skomro, Albert V. Smith, Jennifer E. Smith, J. G. Smith, Nicholas L. Smith, Tanja Smith, Sylvia Smoller, Beverly M. Snively, M Snyder, Tamar Sofer, Nona Sotoodehnia, Adrienne M. Stilp, Garrett Storm, Elizabeth A. Streeten, Jessica Lasky‐Su, Jody Sylvia, Adam A. Szpiro, Daniel Taliun, Hua Tang, Margaret A. Taub, Kent D. Taylor, Matthew R.G. Taylor, Simeon I. Taylor, Marilyn J. Telen, Timothy A. Thornton, Machiko Threlkeld, Lesley F. Tinker, David Tirschwell, Sarah A. Tishkoff, Hemant K. Tiwari, Catherine Tong, Russell P. Tracy, Michael Y. Tsai, Dhananjay Vaidya, David Van Den Berg, Peter VandeHaar, Scott Vrieze, Tarik Walker, Robert L. Wallace, Avram Walts, Fei Fei Wang, Heming Wang, Jiongming Wang, Karol Watson, Jennifer Watt, Daniel E. Weeks, Bruce S. Weir, Scott T. Weiss, Lu‐Chen Weng, Jennifer Wessel, Cristen J. Willer, Kayleen Williams, L. Keoki Williams, Carla G. Wilson, James F. Wilson, Lara Winterkorn, Quenna Wong, Joseph C. Wu, Huichun Xu, Ivana V. Yang, Ketian Yu, Seyedeh M. Zekavat, Yingze Zhang, Snow Xueyan Zhao, Wei Zhao, Xiaofeng Zhu, Michael C. Zody, Sebastian Zoellner, Kai Kammers, Kanika Kanchan, Kruthika Iyer, Madeline H. Kowalski, Achilleas Pitsillides, Bingshan Li, Thorsten M. Schlaeger, Alan R. Shuldiner, Jeffrey R. O’Connell, Nauder Faraday
Bibliographic record
VenueNature Communications · 2021
Typearticle
Languageen
FieldMedicine
TopicPlatelet Disorders and Treatments
Canadian institutionsUniversity of SaskatchewanUniversité de MontréalUniversité LavalUniversity of OttawaUniversity of CalgaryProvidence Health Care
FundersNational Center for Research ResourcesNational Institute of General Medical SciencesNational Human Genome Research InstituteNational Heart, Lung, and Blood InstituteMedical Research CouncilNational Institute on AgingNational Blood FoundationUniversity of BristolEuropean CommissionBroad InstituteNational Institute of Diabetes and Digestive and Kidney DiseasesJohns Hopkins UniversityNational Institutes of HealthU.S. Department of Health and Human Services
KeywordsGenome-wide association studyExpression quantitative trait lociLocus (genetics)BiologyQuantitative trait locusGeneticsGenePlatelet activationPhenotypeGenomeRegulatorBioinformaticsComputational biologySingle-nucleotide polymorphismPlateletImmunology
Abstract
Platelet aggregation at the site of atherosclerotic vascular injury is the underlying pathophysiology of myocardial infarction and stroke. To build upon prior GWAS, here we report on 16 loci identified through a whole genome sequencing (WGS) approach in 3,855 NHLBI Trans-Omics for Precision Medicine (TOPMed) participants deeply phenotyped for platelet aggregation. We identify the RGS18 locus, which encodes a myeloerythroid lineage-specific regulator of G-protein signaling that co-localizes with expression quantitative trait loci (eQTL) signatures for RGS18 expression in platelets. Gene-based approaches implicate the SVEP1 gene, a known contributor of coronary artery disease risk. Sentinel variants at RGS18 and PEAR1 are associated with thrombosis risk and increased gastrointestinal bleeding risk, respectively. Our WGS findings add to previously identified GWAS loci, provide insights regarding the mechanism(s) by which genetics may influence cardiovascular disease risk, and underscore the importance of rare variant and regulatory approaches to identifying loci contributing to complex phenotypes.
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 imitationNot 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 score0.772
Threshold uncertainty score0.342
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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 head0.025
GPT teacher head0.297
Teacher spread0.272 · 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 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
Citations54
Published2021
Admission routes1
Has abstractyes