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Whole genome sequence analysis of blood lipid levels in >66,000 individuals
Margaret Sunitha Selvaraj, Xihao Li, Zilin Li, Akhil Pampana, David Zhang, Joseph Park, Stella Aslibekyan, Joshua C. Bis, Jennifer A. Brody, Brian E. Cade, Lee‐Ming Chuang, Ren‐Hua Chung, Joanne E. Curran, Lisa de las Fuentes, Paul S. de Vries, Ravindranath Duggirala, Barry I. Freedman, Mariaelisa Graff, Xiuqing Guo, Nancy L. Heard‐Costa, Bertha Hidalgo, Chii‐Min Hwu, Marguerite R. Irvin, Tanika N. Kelly, Brian G. Kral, Leslie A. Lange, Xiaohui Li, Martin Lisa, Steven A. Lubitz, Ani Manichaikul, Michael Preuß, May E. Montasser, Alanna C. Morrison, Take Naseri, Jeffrey R. O’Connell, Patricia A. Peyser, Muagututi‘a Sefuiva Reupena, Jennifer A. Smith, Xiao Sun, Kent D. Taylor, Russell P. Tracy, Michael Y. Tsai, Zhe Wang, Yuxuan Wang, Wei Bao, John T. Wilkins, Lisa R. Yanek, Wei Zhao, Donna K. Arnett, John Blangero, Eric Boerwinkle, Donald W. Bowden, Yii‐Der Ida Chen, Adolfo Correa, L. Adrienne Cupples, Susan K. Dutcher, Patrick T. Ellinor, Myriam Fornage, Stacey Gabriel, Søren Germer, Richard A. Gibbs, Jiang He, Robert C. Kaplan, Sharon L. R. Kardia, Ryan Kim, Charles Kooperberg, Ruth J. F. Loos, Karine A. Viaud‐Martinez, Rasika A. Mathias, Stephen T. McGarvey, Braxton D. Mitchell, Deborah A. Nickerson, Kari E. North, Bruce M. Psaty, Susan Redline, Alex P. Reiner, Ramachandran S. Vasan, Stephen S. Rich, Cristen J. Willer, Jerome I. Rotter, Daniel J. Rader, Xihong Lin, Namiko Abe, Gonçalo R. Abecasis, François Aguet, Christine M. Albert, Laura Almasy, Álvaro Alonso, Seth A. Ament, Peter Anderson, Pramod Anugu, Deborah Applebaum‐Bowden, Kristin Ardlie, Dan E. Arking, Allison E. Ashley‐Koch, 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 H. Beaty, Gerald J. Beck, Diane M. Becker, Lewis C. Becker, Rebecca Beer, Amber L. Beitelshees, Emelia J. Benjamin, Takis Benos, Marcos Bezerra, Larry Bielak, Thomas W. Blackwell, Russell P. Bowler, Ulrich Broeckel, Jai Broome, Deborah Brown, Karen Bunting, Esteban G. Burchard, Carlos D. Bustamante, Erin Buth, 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, Michael Cho, Seung Hoan Choi, Mina K. Chung, Clary B. Clish, Suzy Comhair, Matthew P. Conomos, Elaine Cornell, Carolyn Crandall, James D. Crapo, Jeffrey L. Curtis, Brian Custer, Coleen Damcott, Dawood Darbar, Sean P. David, Colleen Davis, Michelle Daya, Mariza de Andrade, 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, Charles Eaton, Lynette Ekunwe, Adel Boueiz, Leslie S. Emery, Serpil C. Erzurum, Charles R. Farber, Jesse Farek, Tasha E. Fingerlin, Matthew Flickinger, Nora Franceschini, Chris Frazar, Mao Fu, Stephanie M. Fullerton, Lucinda Fulton, Weiniu Gan, Shanshan Gao, Yan Gao, Margery Gass, Heather Geiger, Bruce D. Gelb, Mark W. Geraci, Robert E. Gerszten, Auyon Ghosh, 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, Namrata Gupta, David M. Haas, Jeff Haessler, Michael E. Hall, Yi Han, Patrick J. Hanly, Daniel Harris, Nicola L. Hawley, Ben Heavner, Susan R. Heckbert, Ryan D. Hernandez, David M. Herrington, Craig P. Hersh, James E. Hixson, Brian D. Hobbs, John E. Hokanson, Elliott Hong, Karin F. Hoth, Chao A. Hsiung, Jianhong Hu, Yi‐Jen Hung, Haley Huston, Chii Min Hwu, Rebecca D. Jackson, Deepti Jain, Cashell E. Jaquish, Jill M. Johnsen, Andrew M. Johnson, Craig Johnson, Rich Johnston, Kimberly Jones, Hyun Min Kang, Shannon Kelly, Eimear E. Kenny, Michael D. Kessler, Alyna Khan, Ziad Khan, Wonji Kim, John Kimoff, Gregory L. Kinney, Barbara A. Konkle, Holly Kramer, Christoph Lange, Ethan M. Lange, Cathy C. Laurie, Cecelia Laurie, Meryl S. LeBoff, Jiwon Lee, Sandra Lee, Wen‐Jane Lee, Jonathon LeFaive, David Levine, Dan Levy, Joshua P. Lewis, Yun Li, Henry J. Lin, Honghuang Lin, Simin Liu, Yongmei Liu, Yu Liu, Kathryn L. Lunetta, James Luo, Ulysses J. Magalang, Michael C. Mahaney, Barry J. Make, Alisa K. Manning, JoAnn E. Manson, Lisa W. Martin, Melissa Marton, Susan Mathai, Susanne May, Patrick F. McArdle, Merry‐Lynn McDonald, Sean McFarland, 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, Matt Moll, Zeineen Momin, Courtney G. Montgomery, Donna M. Muzny, Josyf C. Mychaleckyj, Girish N. Nadkarni, Rakhi P. Naik, Sergeï Nekhai, Sarah C. Nelson, Bonnie Neltner, Caitlin Nessner, Osuji Nkechinyere, Jeff O’Connell, Tim O’Connor, Heather M. Ochs‐Balcom, Geoffrey Okwuonu, Allan I Pack, David T. Paik, James S. Pankow, George Papanicolaou, Juan M. Peralta, Marco Perez, James A. Perry, Ulrike Peters, Lawrence S. Phillips, Jacob Pleiness, Toni I. Pollin, Wendy S. Post, Julia Powers Becker, Meher Preethi Boorgula, Pankaj Qasba, Dandi Qiao, Zhaohui Qin, Nicholas Rafaels, Laura M. Raffield, Mahitha Rajendran, D. C. Rao, Laura J. Rasmussen‐Torvik, Aakrosh Ratan, Robert M. Reed, Catherine Reeves, Elizabeth A. Regan, Kenneth Rice, Rébecca Robillard, Nicolas Robine, Dan M. Roden, Carolina Roselli, Ingo Ruczinski, Alexi Runnels, Pamela Russell, Sarah Ruuska, Kathleen A. Ryan, Éster Cerdeira Sabino, Danish Saleheen, Shabnam Salimi, Sejal Salvi, Steven L. Salzberg, Kevin Sandow, Vijay G. Sankaran, Jireh Santibanez, Karen Schwander, David Schwartz, Frank C. Sciurba, Christine E. 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, J. G. Smith, Nicholas H. 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, Matthew R.G. Taylor, Simeon I. Taylor, Marilyn J. Telen, Timothy A. Thornton, Machiko Threlkeld, Lesley Tinker, David Tirschwell, Sarah A. Tishkoff, Hemant K. Tiwari, Catherine Tong, Dhananjay Vaidya, David Van Den Berg, Peter VandeHaar, Scott Vrieze, Tarik Walker, Robert B. Wallace, Avram Walts, Fei Fei Wang, Heming Wang, Jiongming Wang, Karol E. Watson, Jennifer Watt, Daniel E. Weeks, Joshua Weinstock, Bruce S. Weir, Scott T. Weiss, Lu‐Chen Weng, Jennifer Wessel, Kayleen Williams, L. Keoki Williams, Carla Wilson, James G. Wilson, Lara Winterkorn, Quenna Wong, Joseph Wu, Huichun Xu, Ivana V. Yang, Ketian Yu, Seyedeh M. Zekavat, Yingze Zhang, Snow Xueyan Zhao, Xiaofeng Zhu, Michael C. Zody, Sebastian Zoellner, Gina M. Peloso, Pradeep Natarajan
Bibliographic record
VenueNature Communications · 2022
Typearticle
Languageen
FieldMedicine
TopicLipoproteins and Cardiovascular Health
Canadian institutionsUniversity of SaskatchewanUniversité de MontréalUniversité LavalUniversity of OttawaMcGill UniversityUniversity of Calgary
FundersNational Institute of Environmental Health SciencesNational Human Genome Research InstituteNational Institute on AgingNational Cancer InstituteScience and Technology Facilities CouncilBoston Scientific CorporationNovo Nordisk FondenYale UniversityInvitaeBristol-Myers SquibbAstraZenecaNational Institute of Mental HealthNational Heart, Lung, and Blood InstitutePfizerNational Institute of Diabetes and Digestive and Kidney DiseasesAmgenRegeneron PharmaceuticalsU.S. Department of Veterans AffairsNational Institutes of HealthU.S. Department of Health and Human Services
KeywordsGeneticsBiologyGeneMendelian inheritanceWhole genome sequencingDyslipidemiaGenomeAlleleComputational biologyGenome-wide association studySingle-nucleotide polymorphismGenotypeEndocrinology
Abstract
Blood lipids are heritable modifiable causal factors for coronary artery disease. Despite well-described monogenic and polygenic bases of dyslipidemia, limitations remain in discovery of lipid-associated alleles using whole genome sequencing (WGS), partly due to limited sample sizes, ancestral diversity, and interpretation of clinical significance. Among 66,329 ancestrally diverse (56% non-European) participants, we associate 428M variants from deep-coverage WGS with lipid levels; ~400M variants were not assessed in prior lipids genetic analyses. We find multiple lipid-related genes strongly associated with blood lipids through analysis of common and rare coding variants. We discover several associated rare non-coding variants, largely at Mendelian lipid genes. Notably, we observe rare LDLR intronic variants associated with markedly increased LDL-C, similar to rare LDLR exonic variants. In conclusion, we conducted a systematic whole genome scan for blood lipids expanding the alleles linked to lipids for multiple ancestries and characterize a clinically-relevant rare non-coding variant model for lipids.
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)0.001
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: Observational · Consensus signal: Observational
GenreCandidate signal: Empirical · Consensus signal: Empirical
Teacher disagreement score0.251
Threshold uncertainty score0.556
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.003 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.001 |
| 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 head0.042
GPT teacher head0.328
Teacher spread0.287 · 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 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
Citations74
Published2022
Admission routes1
Has abstractyes