Deep-coverage whole genome sequences and blood lipids among 16,324 individuals

著者: Pradeep Natarajan, Gina M. Peloso, Seyedeh M. Zekavat, May E. Montasser, Andrea Ganna, Mark Chaffin, Amit V. Khera, Wei Zhou, Jonathan M. Bloom, J Engreitz, Jason Ernst, Jeffrey R. O’Connell, Sanni Ruotsalainen, Maris Alver, Ani Manichaikul, W. Craig Johnson, James A. Perry, Timothy Poterba, Cotton Seed, Ida Surakka, Tõnu Esko, Samuli Ripatti, Veikko Salomaa, Adolfo Correa, Ramachandran S. Vasan, Manolis Kellis, Benjamin M. Neale, Eric S. Lander, Gonçalo R. Abecasis, Braxton D. Mitchell, Stephen S. Rich, James G. Wilson, L. Adrienne Cupples, Jerome I. Rotter, Cristen J. Willer, Sekar Kathiresan, NHLBI TOPMed Lipids Working Group, Namiko Abe, Christine M. Albert, Nicholette Palmer Allred, Laura Almasy, Álvaro Alonso, Seth A. Ament, Peter Anderson, Pramod Anugu, Deborah Applebaum‐Bowden, Dan E. Arking, Donna K. Arnett, Allison E. Ashley‐Koch, Stella Aslibekyan, Tim Assimes, Paul L. Auer, Dimitrios Avramopoulos, J. A. Barnard, Kathleen C. Barnes, R. Graham Barr, Emily Barron‐Casella, Terri H. Beaty, Diane M. Becker, Lewis C. Becker, Rebecca Beer, Ferdouse Begum, Amber L. Beitelshees, Emelia J. Benjamin, Marcos Bezerra, Larry Bielak, Joshua C. Bis, Thomas W. Blackwell, John Blangero, Eric Boerwinkle, Ingrid B. Borecki, Russell P. Bowler, Jennifer A. Brody, Ulrich Broeckel, Jai Broome, Karen Bunting, Esteban Burchard, Jonathan Cardwell, Cara L. Carty, Richard Casaburi, James F. Casella, Christy Chang, Daniel I. Chasman, Sameer Chavan, Bo-Juen Chen, Wei‐Min Chen, Yii-Der Ida Chen, Michael H. Cho, Seung Hoan Choi, Lee‐Ming Chuang, Mina K. Chung, Elaine Cornell, Carolyn Crandall, James D. Crapo, Joanne E. Curran, Jeffrey L. Curtis, Brian Custer, Coleen Damcott, Dawood Darbar, Sayantan Das, Sean P. David, Colleen Davis, Michelle Daya, Mariza de Andrade, Michael R. DeBaun, Ranjan Deka, Dawn L. DeMeo, Scott E. Devine, Ron Do, Qing Duan, Ravi Duggirala, Peter Durda, Susan K. Dutcher, Charles B. Eaton, Lynette Ekunwe, Patrick T. Ellinor, Leslie S. Emery, Charles R. Farber, Leanna Farnam, Tasha E. Fingerlin, Matthew Flickinger, Myriam Fornage, Nora Franceschini, Mao Fu, Malia Fullerton, Lucinda A. Fulton, Stacey Gabriel, Weiniu Gan, Yan Gao, Margery Gass, Bruce D. Gelb, Xiaoqi Geng, Søren Germer, Chris Gignoux, Mark T. Gladwin, David C. Glahn, Stephanie M. Gogarten, Da‐Wei Gong, Harald H.H. Göring, C. Charles Gu, Yue Guan, Xiuqing Guo, Jeff Haessler, Michael E. Hall, Daniel Harris, Nicola L. Hawley, Jiang He, Ben Heavner, Susan R. Heckbert, Ryan D. Hernandez, David M. Herrington, Craig P. Hersh, Bertha Hidalgo, James E. Hixson, John S. Hokanson, Elliott Hong, Karin F. Hoth, Chao A. Hsiung, Haley Huston, Chii Min Hwu, Marguerite R. Irvin, Rebecca Jackson, Deepti Jain, Cashell E. Jaquish, Min A. Jhun, Jill M. Johnsen, Andrew D. Johnson, Rich Johnston, Kimberly Marie Jones, Hyun Min Kang, Robert C. Kaplan, Sharon L. R. Kardia, Laura J. Kaufman, Shannon Kelly, Eimear E. Kenny, Michael Kessler, Alyna Khan, Gregory L. Kinney, Barbara A. Konkle, Charles Kooperberg, Holly Kramer, Stephanie Krauter, Christoph Lange, Ethan M. Lange, Leslie A. Lange, Cathy C. Laurie, Cecelia Laurie, Meryl S. LeBoff, Seunggeun Shawn Lee, Wen‐Jane Lee, Jonathon LeFaive, David Levine, Daniel Levy, Joshua R. Lewis, Yun Li, Honghuang Lin, Keng Han Lin, Simin Liu, Yongmei Liu, Ruth J. F. Loos, Steven A. Lubitz, Kathryn L. Lunetta, James Luo, Michael C. Mahaney, Barry J. Make, JoAnn E. Manson, Lauren Margolin, Lisa W. Martin, Susan Mathai, Rasika A. Mathias, Patrick F. McArdle, Merry‐Lynn McDonald, Sean McFarland, Stephen T. McGarvey, Hao Mei, Deborah A. Meyers, Julie Mikulla, Yuan‐I Min, Mollie Minear, Ryan L. Minster, Solomon K. Musani, Stanford Mwasongwe, Josyf C. Mychaleckyj, Girish N. Nadkarni, Rakhi P. Naik, Sergeï Nekhai, Deborah A. Nickerson, Kari North, Tim O’Connor, Heather M. Ochs‐Balcom, James S. Pankow, George Papanicolaou, Margaret M. Parker, Afshin Parsa, Sara Penchev, Juan M. Peralta, Marco Perez, Ulrike Peters, Patricia A. Peyser, Larry Phillips, Sam Phillips, Toni I. Pollin, Wendy S. Post, Julia Powers Becker, Meher Preethi Boorgula, Michael Preuß, Dmitry Prokopenko, Bruce M. Psaty, Pankaj Qasba, Dandi Qiao, Zhaohui Qin, Nicholas Rafaels, Laura M. Raffield, D. C. Rao, Laura J. Rasmussen‐Torvik, Aakrosh Ratan, Susan Redline, Robert D. Reed, Elizabeth Regan, Alex P. Reiner, Kenneth Rice, Dan M. Roden, Carolina Roselli, Ingo Ruczinski, Pamela Russell, Sarah Ruuska, Kathleen A. Ryan, Phuwanat Sakornsakolpat, Shabnam Salimi, Steven L. Salzberg, Kevin Sandow, Vijay G. Sankaran, Ellen M. Schmidt, Karen Schwander, David Schwartz, Frank C. Sciurba, Christine E. Seidman, Vivien Sheehan, Amol C. Shetty, Aniket Shetty, Wayne Hui-Heng Sheu, M. Benjamin Shoemaker, Brian Silver, Edwin K. Silverman, Jennifer A. Smith, Josh Smith, Nicholas L. Smith, Tanja Smith, Sylvia Smoller, Beverly M. Snively, Tamar Sofer, Nona Sotoodehnia, Adrienne M. Stilp, Elizabeth A. Streeten, Yun Ju Sung, Jody Sylvia, Adam A. Szpiro, Carole Sztalryd, Daniel Taliun, Hua Tang, Margaret A. Taub, Kent D. Taylor, Simeon I. Taylor, Marilyn J. Telen, Timothy Thornton, Lesley F. Tinker, David Tirschwell, Hemant K. Tiwari, Russell P. Tracy, Michael Tsai, Dhananjay Vaidya, Peter VandeHaar, Scott Vrieze, Tarik Walker, Robert K. Wallace, Avram Walts, Emily S. Wan, Fei Fei Wang, Karol Watson, Daniel E. Weeks, B. S. Weir, Scott T. Weiss, Lu‐Chen Weng, Cristen J. Willer, Kayleen Williams, L. Keoki Williams, Carla Wilson, Quenna Wong, Huichun Xu, Lisa R. Yanek, Ivana V. Yang, Rongze Yang, Norann A. Zaghloul, Yingze Zhang, Snow Xueyan Zhao, Xiuwen Zheng, Degui Zhi, Xiang Zhou, Michael C. Zody, Sebastian Zoellner - Nature Communications 2018 被引用: 200

Large-scale deep-coverage whole-genome sequencing (WGS) is now feasible and offers potential advantages for locus discovery. We perform WGS in 16,324 participants from four ancestries at mean depth >29X and analyze genotypes with four quantitative traits-plasma total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides. Common variant association yields known loci except for few variants previously poorly imputed. Rare coding variant association yields known Mendelian dyslipidemia genes but rare non-coding variant association detects no signals. A high 2M-SNP LDL-C polygenic score (top 5th percentile) confers similar effect size to a monogenic mutation (~30 mg/dl higher for each); however, among those with severe hypercholesterolemia, 23% have a high polygenic score and only 2% carry a monogenic mutation. At these sample sizes and for these phenotypes, the incremental value of WGS for discovery is limited but WGS permits simultaneous assessment of monogenic and polygenic models to severe hypercholesterolemia.