Whole genome sequence analysis of blood lipid levels in >66,000 individuals

Margaret Sunitha Selvaraj; Xihao Li; Zilin Li; Akhil Pampana; David Y 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 Heard-Costa; Bertha Hidalgo; Chii-Min Hwu; Marguerite R Irvin; Tanika N Kelly; Brian G Kral; Leslie Lange; Xiaohui Li; Martin Lisa; Steven A Lubitz; Ani W Manichaikul; Preuss Michael; May E Montasser; Alanna C Morrison; Take Naseri; Jeffrey R O'Connell; Nicholette D Palmer; Patricia A Peyser; Muagututia S 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; Soren Germer; Richard 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 Nickerson; Kari E North; Bruce M Psaty; Susan Redline; Alexander P Reiner; Ramachandran S Vasan; Stephen S Rich; Cristen Willer; Jerome I Rotter; Daniel J Rader; Xihong Lin; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium; Gina M Peloso; Pradeep Natarajan

doi:10.1038/s41467-022-33510-7

Whole genome sequence analysis of blood lipid levels in >66,000 individuals

Nat Commun. 2022 Oct 11;13(1):5995. doi: 10.1038/s41467-022-33510-7.

Authors

Margaret Sunitha Selvaraj^{1

2

3}, Xihao Li⁴, Zilin Li⁴, Akhil Pampana², David Y Zhang^{5

6}, Joseph Park^{5

6}, Stella Aslibekyan⁷, Joshua C Bis⁸, Jennifer A Brody⁸, Brian E Cade⁹, Lee-Ming Chuang¹⁰, Ren-Hua Chung¹¹, Joanne E Curran¹², Lisa de Las Fuentes^{13

14}, Paul S de Vries¹⁵, Ravindranath Duggirala¹², Barry I Freedman¹⁶, Mariaelisa Graff¹⁷, Xiuqing Guo¹⁸, Nancy Heard-Costa¹⁹, Bertha Hidalgo⁷, Chii-Min Hwu²⁰, Marguerite R Irvin⁷, Tanika N Kelly^{21

22}, Brian G Kral²³, Leslie Lange²⁴, Xiaohui Li¹⁸, Martin Lisa²⁵, Steven A Lubitz^{1

26}, Ani W Manichaikul²⁷, Preuss Michael²⁸, May E Montasser²⁹, Alanna C Morrison¹⁵, Take Naseri³⁰, Jeffrey R O'Connell²⁹, Nicholette D Palmer³¹, Patricia A Peyser³², Muagututia S Reupena³³, Jennifer A Smith³², Xiao Sun²¹, Kent D Taylor¹⁸, Russell P Tracy³⁴, Michael Y Tsai³⁵, Zhe Wang²⁸, Yuxuan Wang³⁶, Wei Bao³⁷, John T Wilkins³⁸, Lisa R Yanek²³, Wei Zhao³², Donna K Arnett³⁹, John Blangero¹², Eric Boerwinkle¹⁵, Donald W Bowden³¹, Yii-Der Ida Chen⁴⁰, Adolfo Correa⁴¹, L Adrienne Cupples³⁶, Susan K Dutcher⁴², Patrick T Ellinor^{1

26}, Myriam Fornage⁴³, Stacey Gabriel⁴⁴, Soren Germer⁴⁵, Richard Gibbs⁴⁶, Jiang He^{21

22}, Robert C Kaplan^{47

48}, Sharon L R Kardia³², Ryan Kim⁴⁹, Charles Kooperberg⁴⁸, Ruth J F Loos^{28

50}, Karine A Viaud-Martinez⁵¹, Rasika A Mathias²³, Stephen T McGarvey⁵², Braxton D Mitchell^{29

53}, Deborah Nickerson⁵⁴, Kari E North¹⁷, Bruce M Psaty^{8

55

56}, Susan Redline⁹, Alexander P Reiner^{48

55}, Ramachandran S Vasan^{57

58

59}, Stephen S Rich²⁷, Cristen Willer⁶⁰, Jerome I Rotter¹⁸, Daniel J Rader^{5

6

61}, Xihong Lin^{2

4

62}; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium; Gina M Peloso⁶³, Pradeep Natarajan^{64

65

66}

Collaborators

NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium:
Namiko Abe, Gonçalo Abecasis, Francois Aguet, Christine Albert, Laura Almasy, Alvaro Alonso, Seth Ament, Peter Anderson, Pramod Anugu, Deborah Applebaum-Bowden, Kristin Ardlie, Dan Arking, Allison Ashley-Koch, Tim Assimes, Paul Auer, Dimitrios Avramopoulos, Najib Ayas, Adithya Balasubramanian, John Barnard, Kathleen Barnes, R Graham Barr, Emily Barron-Casella, Lucas Barwick, Terri Beaty, Gerald Beck, Diane Becker, Lewis Becker, Rebecca Beer, Amber Beitelshees, Emelia Benjamin, Takis Benos, Marcos Bezerra, Larry Bielak, Thomas Blackwell, Russell Bowler, Ulrich Broeckel, Jai Broome, Deborah Brown, Karen Bunting, Esteban Burchard, Carlos Bustamante, Erin Buth, Jonathan Cardwell, Vincent Carey, Julie Carrier, Cara Carty, Richard Casaburi, Juan P Casas Romero, James Casella, Peter Castaldi, Mark Chaffin, Christy Chang, Yi-Cheng Chang, Daniel Chasman, Sameer Chavan, Bo-Juen Chen, Wei-Min Chen, Yii-Der Ida Chen, Michael Cho, Seung Hoan Choi, Mina Chung, Clary Clish, Suzy Comhair, Matthew Conomos, Elaine Cornell, Carolyn Crandall, James Crapo, L Adrienne Cupples, Jeffrey Curtis, Brian Custer, Coleen Damcott, Dawood Darbar, Sean David, Colleen Davis, Michelle Daya, Mariza de Andrade, Michael DeBaun, Ranjan Deka, Dawn DeMeo, Scott Devine, Huyen Dinh, Harsha Doddapaneni, Qing Duan, Shannon Dugan-Perez, Ravi Duggirala, Jon Peter Durda, Charles Eaton, Lynette Ekunwe, Adel El Boueiz, Leslie Emery, Serpil Erzurum, Charles Farber, Jesse Farek, Tasha 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 Gelb, Mark Geraci, Robert Gerszten, Auyon Ghosh, Chris Gignoux, Mark Gladwin, David Glahn, Stephanie Gogarten, Da-Wei Gong, Harald Goring, Sharon Graw, Kathryn J Gray, Daniel Grine, Colin Gross, C Charles Gu, Yue Guan, Namrata Gupta, David M Haas, Jeff Haessler, Michael Hall, Yi Han, Patrick Hanly, Daniel Harris, Nicola L Hawley, Ben Heavner, Susan Heckbert, Ryan Hernandez, David Herrington, Craig Hersh, Bertha Hidalgo, James Hixson, Brian Hobbs, John Hokanson, Elliott Hong, Karin Hoth, Chao Agnes Hsiung, Jianhong Hu, Yi-Jen Hung, Haley Huston, Chii Min Hwu, Rebecca Jackson, Deepti Jain, Cashell Jaquish, Jill Johnsen, Andrew Johnson, Craig Johnson, Rich Johnston, Kimberly Jones, Hyun Min Kang, Shannon Kelly, Eimear Kenny, Michael Kessler, Alyna Khan, Ziad Khan, Wonji Kim, John Kimoff, Greg Kinney, Barbara Konkle, Holly Kramer, Christoph Lange, Ethan Lange, Cathy Laurie, Cecelia Laurie, Meryl LeBoff, Jiwon Lee, Sandra Lee, Wen-Jane Lee, Jonathon LeFaive, David Levine, Dan Levy, Joshua Lewis, Yun Li, Henry Lin, Honghuang Lin, Simin Liu, Yongmei Liu, Yu Liu, Kathryn Lunetta, James Luo, Ulysses Magalang, Michael Mahaney, Barry Make, Alisa Manning, JoAnn Manson, Lisa Martin, Melissa Marton, Susan Mathai, Susanne May, Patrick McArdle, Merry-Lynn McDonald, Sean McFarland, Daniel McGoldrick, Caitlin McHugh, Becky McNeil, Hao Mei, James Meigs, Vipin Menon, Luisa Mestroni, Ginger Metcalf, Deborah A Meyers, Emmanuel Mignot, Julie Mikulla, Nancy Min, Mollie Minear, Ryan L Minster, Matt Moll, Zeineen Momin, Courtney Montgomery, Donna Muzny, Josyf C Mychaleckyj, Girish Nadkarni, Rakhi Naik, Sergei Nekhai, Sarah C Nelson, Bonnie Neltner, Caitlin Nessner, Osuji Nkechinyere, Jeff O'Connell, Tim O'Connor, Heather Ochs-Balcom, Geoffrey Okwuonu, Allan Pack, David T Paik, James Pankow, George Papanicolaou, Cora Parker, Juan Manuel Peralta, Marco Perez, James Perry, Ulrike Peters, Lawrence S Phillips, Jacob Pleiness, Toni Pollin, Wendy Post, Julia Powers Becker, Meher Preethi Boorgula, Michael Preuss, Pankaj Qasba, Dandi Qiao, Zhaohui Qin, Nicholas Rafaels, Laura Raffield, Mahitha Rajendran, Ramachandran S Vasan, D C Rao, Laura Rasmussen-Torvik, Aakrosh Ratan, Robert Reed, Catherine Reeves, Elizabeth Regan, Alex Reiner, Ken Rice, Rebecca Robillard, Nicolas Robine, Dan Roden, Carolina Roselli, Ingo Ruczinski, Alexi Runnels, Pamela Russell, Sarah Ruuska, Kathleen Ryan, Ester Cerdeira Sabino, Danish Saleheen, Shabnam Salimi, Sejal Salvi, Steven Salzberg, Kevin Sandow, Vijay G Sankaran, Jireh Santibanez, Karen Schwander, David Schwartz, Frank Sciurba, Christine Seidman, Jonathan Seidman, Frédéric Sériès, Vivien Sheehan, Stephanie L Sherman, Amol Shetty, Aniket Shetty, Wayne Hui-Heng Sheu, M Benjamin Shoemaker, Brian Silver, Edwin Silverman, Robert Skomro, Albert Vernon Smith, Josh Smith, Nicholas Smith, Tanja Smith, Sylvia Smoller, Beverly Snively, Michael Snyder, Tamar Sofer, Nona Sotoodehnia, Adrienne M Stilp, Garrett Storm, Elizabeth Streeten, Jessica Lasky Su, Yun Ju Sung, Jody Sylvia, Adam Szpiro, Daniel Taliun, Hua Tang, Margaret Taub, Matthew Taylor, Simeon Taylor, Marilyn Telen, Timothy A Thornton, Machiko Threlkeld, Lesley Tinker, David Tirschwell, Sarah Tishkoff, Hemant Tiwari, Catherine Tong, Dhananjay Vaidya, David Van Den Berg, Peter VandeHaar, Scott Vrieze, Tarik Walker, Robert Wallace, Avram Walts, Fei Fei Wang, Heming Wang, Jiongming Wang, Karol Watson, Jennifer Watt, Daniel E Weeks, Joshua Weinstock, Bruce Weir, Scott T Weiss, Lu-Chen Weng, Jennifer Wessel, Kayleen Williams, L Keoki Williams, Carla Wilson, James Wilson, Lara Winterkorn, Quenna Wong, Joseph Wu, Huichun Xu, Ivana Yang, Ketian Yu, Seyedeh Maryam Zekavat, Yingze Zhang, Snow Xueyan Zhao, Wei Zhao, Xiaofeng Zhu, Michael Zody, Sebastian Zoellner

Affiliations

¹ Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, 02114, USA.
² Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.
³ Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA.
⁴ Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.
⁵ Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
⁶ Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
⁷ Department of Epidemiology, University of Alabama at Birmingham School of Public Health, Birmingham, AL, USA.
⁸ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
⁹ Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
¹⁰ Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
¹¹ Institute of Population Health Sciences, National Health Research Institutes, Zhunan, 350, Taiwan.
¹² Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, 78520, USA.
¹³ Department of Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, MO, USA.
¹⁴ Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA.
¹⁵ Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
¹⁶ Department of Internal Medicine, Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
¹⁷ Department of Epidemiology, UNC Chapel Hill, Chapel Hill, NC, USA.
¹⁸ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
¹⁹ Department of Neurology, Boston university School of Medicine, Boston, MA, USA.
²⁰ Section of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
²¹ Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, 70112, USA.
²² Tulane University Translational Science Institute, New Orleans, LA, 70112, USA.
²³ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
²⁴ Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
²⁵ Department of Medicine, George Washington University, Washingron, DC, USA.
²⁶ Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, 02124, USA.
²⁷ Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
²⁸ The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²⁹ Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
³⁰ Ministry of Health, Government of Samoa, Samoa, USA.
³¹ Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
³² Department of Epidemiology, University of Michigan, Ann Arbor, MI, 48109, USA.
³³ Lutia i Puava ae Mapu i Fagalele, Apia, Samoa.
³⁴ Departments of Pathology & Laboratory Medicine and Biochemistry, Larner College of Medicine at the University of Vermont, Colchester, VT, USA.
³⁵ Department of Laboratory Medicine and Pathology, University of Minneosta, Minneapolis, MN, USA.
³⁶ Department of Biostatistics, Boston University School of Public Health, Boston, MA, 02118, USA.
³⁷ Institute of Public Health, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230026, China.
³⁸ Department of Medicine (Cardiology) and Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
³⁹ Dean's Office, University of Kentucky College of Public Health, Lexington, KY, USA.
⁴⁰ Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
⁴¹ Department of Population Health Science, University of Mississippi Medical Center, Jackson, MS, USA.
⁴² The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, 63108, USA.
⁴³ Brown Foundation Institute of Molecular Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 7722, USA.
⁴⁴ Broad Institute, Cambridge, MA, 02142, USA.
⁴⁵ New York Genome Center, New York, NY, 10013, USA.
⁴⁶ Baylor College of Medicine Human Genome Sequencing Center, Houston, TX, 77030, USA.
⁴⁷ Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
⁴⁸ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.
⁴⁹ Psomagen, Inc. (formerly Macrogen USA), Rockville, MD, USA.
⁵⁰ NNF Center for Basic Metabolic Research, University of Copenhagen, Cophenhagen, Denmark.
⁵¹ Illumina Laboratory Services, Illumina. Inc, San Diego, 92122, USA.
⁵² Department of Epidemiology, International Health Institute, Brown University, Providence, RI, USA.
⁵³ Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD, USA.
⁵⁴ University of Washington, Department of Genome Sciences, Seattle, WA, 98195, USA.
⁵⁵ Department of Epidemiology, University of Washington, Seattle, WA, USA.
⁵⁶ Department of Health Systems and Population Health, University of Washington, Seattle, WA, USA.
⁵⁷ Sections of Preventive medicine and Epidemiology, Cardiovascular medicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
⁵⁸ Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.
⁵⁹ Framingham Heart Study, Framingham, MA, USA.
⁶⁰ University of Michigan, Internal Medicine, Ann Arbor, MI, 48109, USA.
⁶¹ Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
⁶² Department of Statistics, Harvard University, Cambridge, MA, 02138, USA.
⁶³ Department of Biostatistics, Boston University School of Public Health, Boston, MA, 02118, USA. gpeloso@bu.edu.
⁶⁴ Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, 02114, USA. pnatarajan@mgh.harvard.edu.
⁶⁵ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA. pnatarajan@mgh.harvard.edu.
⁶⁶ Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA. pnatarajan@mgh.harvard.edu.

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Alleles
Cholesterol, LDL
Genome-Wide Association Study*
Humans
Lipids*
Whole Genome Sequencing

Substances

Cholesterol, LDL
Lipids

Abstract

Publication types

MeSH terms

Substances

Grants and funding