Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries

Seyedeh M Zekavat; Sanni Ruotsalainen; Robert E Handsaker; Maris Alver; Jonathan Bloom; Timothy Poterba; Cotton Seed; Jason Ernst; Mark Chaffin; Jesse Engreitz; Gina M Peloso; Ani Manichaikul; Chaojie Yang; Kathleen A Ryan; Mao Fu; W Craig Johnson; Michael Tsai; Matthew Budoff; Ramachandran S Vasan; L Adrienne Cupples; Jerome I Rotter; Stephen S Rich; Wendy Post; Braxton D Mitchell; Adolfo Correa; Andres Metspalu; James G Wilson; Veikko Salomaa; Manolis Kellis; Mark J Daly; Benjamin M Neale; Steven McCarroll; Ida Surakka; Tonu Esko; Andrea Ganna; Samuli Ripatti; Sekar Kathiresan; Pradeep Natarajan; NHLBI TOPMed Lipids Working Group

doi:10.1038/s41467-018-04668-w

Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries

Nat Commun. 2018 Jul 4;9(1):2606. doi: 10.1038/s41467-018-04668-w.

Authors

Seyedeh M Zekavat^{1

2

3}, Sanni Ruotsalainen⁴, Robert E Handsaker^{1

5

6}, Maris Alver^{7

8}, Jonathan Bloom^{1

9}, Timothy Poterba^{1

9}, Cotton Seed^{1

9}, Jason Ernst¹⁰, Mark Chaffin¹, Jesse Engreitz¹, Gina M Peloso¹¹, Ani Manichaikul¹², Chaojie Yang¹², Kathleen A Ryan¹³, Mao Fu¹³, W Craig Johnson¹⁴, Michael Tsai¹⁵, Matthew Budoff¹⁶, Ramachandran S Vasan^{17

18}, L Adrienne Cupples^{11

17}, Jerome I Rotter¹⁹, Stephen S Rich¹², Wendy Post²⁰, Braxton D Mitchell²¹, Adolfo Correa²², Andres Metspalu⁸, James G Wilson²², Veikko Salomaa²³, Manolis Kellis^{1

24}, Mark J Daly^{1

5

9}, Benjamin M Neale^{1

5

9}, Steven McCarroll^{1

5

6}, Ida Surakka⁴, Tonu Esko^{1

8}, Andrea Ganna^{1

5

9}, Samuli Ripatti^{1

4

25}, Sekar Kathiresan^{26

27

28

29}, Pradeep Natarajan^{30

31

32

33}; NHLBI TOPMed Lipids Working Group

Collaborators

NHLBI TOPMed Lipids Working Group:
Namiko Abe, Goncalo Abecasis, Christine Albert, Nicholette Nichole Palmer Allred, Laura Almasy, Alvaro Alonso, Seth Ament, Peter Anderson, Pramod Anugu, Deborah Applebaum-Bowden, Dan Arking, Donna K Arnett, Allison Ashley-Koch, Stella Aslibekyan, Tim Assimes, Paul Auer, Dimitrios Avramopoulos, John Barnard, Kathleen Barnes, R Graham Barr, Emily Barron-Casella, Terri Beaty, Diane Becker, Lewis Becker, Rebecca Beer, Ferdouse Begum, Amber Beitelshees, Emelia Benjamin, Marcos Bezerra, Larry Bielak, Joshua Bis, Thomas Blackwell, John Blangero, Eric Boerwinkle, Ingrid Borecki, Russell Bowler, Jennifer Brody, Ulrich Broeckel, Jai Broome, Karen Bunting, Esteban Burchard, Jonathan Cardwell, Cara Carty, Richard Casaburi, James Casella, Christy Chang, Daniel Chasman, Sameer Chavan, Bo-Juen Chen, Wei-Min Chen, Yii-Der Ida Chen, Michael Cho, Seung Hoan Choi, Lee-Ming Chuang, Mina Chung, Elaine Cornell, Carolyn Crandall, James Crapo, Joanne Curran, Jeffrey Curtis, Brian Custer, Coleen Damcott, Dawood Darbar, Sayantan Das, Sean David, Colleen Davis, Michelle Daya, Mariza de Andrade, Michael DeBaun, Ranjan Deka, Dawn DeMeo, Scott Devine, Ron Do, Qing Duan, Ravi Duggirala, Peter Durda, Susan Dutcher, Charles Eaton, Lynette Ekunwe, Patrick Ellinor, Leslie Emery, Charles Farber, Leanna Farnam, Tasha Fingerlin, Matthew Flickinger, Myriam Fornage, Nora Franceschini, Stephanie M Fullerton, Lucinda Fulton, Stacey Gabriel, Weiniu Gan, Yan Gao, Margery Gass, Bruce Gelb, Xiaoqi Priscilla Geng, Soren Germer, Chris Gignoux, Mark Gladwin, David Glahn, Stephanie Gogarten, Da-Wei Gong, Harald Goring, C Charles Gu, Yue Guan, Xiuqing Guo, Jeff Haessler, Michael Hall, Daniel Harris, Nicola Hawley, Jiang He, Ben Heavner, Susan Heckbert, Ryan Hernandez, David Herrington, Craig Hersh, Bertha Hidalgo, James Hixson, John Hokanson, Elliott Hong, Karin Hoth, Chao Agnes Hsiung, Haley Huston, Chii Min Hwu, Marguerite Ryan Irvin, Rebecca Jackson, Deepti Jain, Cashell Jaquish, Min A Jhun, Jill Johnsen, Andrew Johnson, Rich Johnston, Kimberly Jones, Hyun Min Kang, Robert Kaplan, Sharon Kardia, Laura Kaufman, Shannon Kelly, Eimear Kenny, Michael Kessler, Alyna Khan, Greg Kinney, Barbara Konkle, Charles Kooperberg, Holly Kramer, Stephanie Krauter, Christoph Lange, Ethan Lange, Leslie Lange, Cathy Laurie, Cecelia Laurie, Meryl LeBoff, Seunggeun Shawn Lee, Wen-Jane Lee, Jonathon LeFaive, David Levine, Dan Levy, Joshua Lewis, Yun Li, Honghuang Lin, Keng Han Lin, Simin Liu, Yongmei Liu, Ruth Loos, Steven Lubitz, Kathryn Lunetta, James Luo, Michael Mahaney, Barry Make, JoAnn Manson, Lauren Margolin, Lisa Martin, Susan Mathai, Rasika Mathias, Patrick McArdle, Merry-Lynn McDonald, Sean McFarland, Stephen McGarvey, Hao Mei, Deborah A Meyers, Julie Mikulla, Nancy Min, Mollie Minear, Ryan L Minster, May E Montasser, Solomon Musani, Stanford Mwasongwe, Josyf C Mychaleckyj, Girish Nadkarni, Rakhi Naik, Sergei Nekhai, Deborah Nickerson, Kari North, Jeff O'Connell, Tim O'Connor, Heather Ochs-Balcom, James Pankow, George Papanicolaou, Margaret Parker, Afshin Parsa, Sara Penchev, Juan Manuel Peralta, Marco Perez, James Perry, Ulrike Peters, Patricia Peyser, Larry Phillips, Sam Phillips, Toni Pollin, Julia Powers Becker, Meher Preethi Boorgula, Michael Preuss, Dmitry Prokopenko, Bruce Psaty, Pankaj Qasba, Dandi Qiao, Zhaohui Qin, Nicholas Rafaels, Laura Raffield, D C Rao, Laura Rasmussen-Torvik, Aakrosh Ratan, Susan Redline, Robert Reed, Elizabeth Regan, Alex Reiner, Ken Rice, Dan Roden, Carolina Roselli, Ingo Ruczinski, Pamela Russell, Sarah Ruuska, Phuwanat Sakornsakolpat, Shabnam Salimi, Steven Salzberg, Kevin Sandow, Vijay Sankaran, Christopher Scheller, Ellen Schmidt, Karen Schwander, David Schwartz, Frank Sciurba, Christine Seidman, Vivien Sheehan, Amol Shetty, Aniket Shetty, Wayne Hui-Heng Sheu, M Benjamin Shoemaker, Brian Silver, Edwin Silverman, Jennifer Smith, Josh Smith, Nicholas Smith, Tanja Smith, Sylvia Smoller, Beverly Snively, Tamar Sofer, Nona Sotoodehnia, Adrienne Stilp, Elizabeth Streeten, Yun Ju Sung, Jody Sylvia, Adam Szpiro, Carole Sztalryd, Daniel Taliun, Hua Tang, Margaret Taub, Kent Taylor, Simeon Taylor, Marilyn Telen, Timothy A Thornton, Lesley Tinker, David Tirschwell, Hemant Tiwari, Russell Tracy, Dhananjay Vaidya, Peter VandeHaar, Scott Vrieze, Tarik Walker, Robert Wallace, Avram Walts, Emily Wan, Fei Fei Wang, Karol Watson, Daniel E Weeks, Bruce Weir, Scott Weiss, Lu-Chen Weng, Cristen Willer, Kayleen Williams, L Keoki Williams, Carla Wilson, Quenna Wong, Huichun Xu, Lisa Yanek, Ivana Yang, Rongze Yang, Norann Zaghloul, Yingze Zhang, Snow Xueyan Zhao, Wei Zhao, Xiuwen Zheng, Degui Zhi, Xiang Zhou, Michael Zody, Sebastian Zoellner

Affiliations

¹ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
² Yale School of Medicine, New Haven, CT, 06510, USA.
³ Department of Computational Biology & Bioinformatics, Yale University, New Haven, CT, 06510, USA.
⁴ Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland.
⁵ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
⁶ Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA.
⁷ Department of Biotechnology, Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
⁸ Estonian Genome Center, Tallinn, Estonia.
⁹ Analytic and Translational Genetics Unit, Boston, MA, 02142, USA.
¹⁰ Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
¹¹ Department of Biostatistics, Boston University School of Public Health, Boston, MA, 02118, USA.
¹² Center for Public Health Genomics, University of Virginia, Charlottesville, VA, 22904, USA.
¹³ Program in Personalized and Genomic Medicine, Division of Endocrinology, Diabetes & Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
¹⁴ Department of Biostatistics, School of Public Health and Community Medicine, University of Washington, Seattle, WA, 98195, USA.
¹⁵ Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, 55455, USA.
¹⁶ Division of Cardiology, Harbor-UCLA Medical Center, Los Angeles Biomedical Research Institute, Los Angeles, CA, 90509, USA.
¹⁷ NHLBI Framingham Heart Study, Framingham, MA, 20892, USA.
¹⁸ Sections of Preventive medicine and Epidemiology, and cardiovascular medicine, Departments of Medicine and Epidemiology, Boston university Schools of Medicine and Public health, Boston, MA, 02118, USA.
¹⁹ Departments of Pediatrics and Medicine, The Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, CA, 90509, USA.
²⁰ Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
²¹ Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
²² Department of Medicine, University of Mississippi Medical Center, Jackson, MS, 39216, USA.
²³ National Institute for Health and Welfare, Helsinki, Finland.
²⁴ Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, 32 Vassar St, Cambridge, MA, 02139, USA.
²⁵ Department of Public Health, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
²⁶ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. [email protected].
²⁷ Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA. [email protected].
²⁸ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA. [email protected].
²⁹ Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, 02114, USA. [email protected].
³⁰ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. [email protected].
³¹ Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA. [email protected].
³² Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA. [email protected].
³³ Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, 02114, USA. [email protected].

Abstract

Lipoprotein(a), Lp(a), is a modified low-density lipoprotein particle that contains apolipoprotein(a), encoded by LPA, and is a highly heritable, causal risk factor for cardiovascular diseases that varies in concentrations across ancestries. Here, we use deep-coverage whole genome sequencing in 8392 individuals of European and African ancestry to discover and interpret both single-nucleotide variants and copy number (CN) variation associated with Lp(a). We observe that genetic determinants between Europeans and Africans have several unique determinants. The common variant rs12740374 associated with Lp(a) cholesterol is an eQTL for SORT1 and independent of LDL cholesterol. Observed associations of aggregates of rare non-coding variants are largely explained by LPA structural variation, namely the LPA kringle IV 2 (KIV2)-CN. Finally, we find that LPA risk genotypes confer greater relative risk for incident atherosclerotic cardiovascular diseases compared to directly measured Lp(a), and are significantly associated with measures of subclinical atherosclerosis in African Americans.

MeSH terms

Adaptor Proteins, Vesicular Transport / blood
Adaptor Proteins, Vesicular Transport / genetics
Black People
Black or African American
Cardiovascular Diseases / blood
Cardiovascular Diseases / diagnosis
Cardiovascular Diseases / ethnology
Cardiovascular Diseases / genetics*
Cholesterol, LDL / blood
DNA Copy Number Variations*
Gene Expression
Genome, Human*
Genome-Wide Association Study
Humans
Lipoprotein(a) / blood
Lipoprotein(a) / genetics*
Polymorphism, Single Nucleotide*
Quantitative Trait Loci
Risk Factors
White People
Whole Genome Sequencing

Substances

Adaptor Proteins, Vesicular Transport
Cholesterol, LDL
Lipoprotein(a)
sortilin

Abstract

MeSH terms

Substances

Grants and funding