Dynamic incorporation of multiple in silico functional annotations empowers rare variant association analysis of large whole-genome sequencing studies at scale

Xihao Li; Zilin Li; Hufeng Zhou; Sheila M Gaynor; Yaowu Liu; Han Chen; Ryan Sun; Rounak Dey; Donna K Arnett; Stella Aslibekyan; Christie M Ballantyne; Lawrence F Bielak; John Blangero; Eric Boerwinkle; Donald W Bowden; Jai G Broome; Matthew P Conomos; Adolfo Correa; L Adrienne Cupples; Joanne E Curran; Barry I Freedman; Xiuqing Guo; George Hindy; Marguerite R Irvin; Sharon L R Kardia; Sekar Kathiresan; Alyna T Khan; Charles L Kooperberg; Cathy C Laurie; X Shirley Liu; Michael C Mahaney; Ani W Manichaikul; Lisa W Martin; Rasika A Mathias; Stephen T McGarvey; Braxton D Mitchell; May E Montasser; Jill E Moore; Alanna C Morrison; Jeffrey R O'Connell; Nicholette D Palmer; Akhil Pampana; Juan M Peralta; Patricia A Peyser; Bruce M Psaty; Susan Redline; Kenneth M Rice; Stephen S Rich; Jennifer A Smith; Hemant K Tiwari; Michael Y Tsai; Ramachandran S Vasan; Fei Fei Wang; Daniel E Weeks; Zhiping Weng; James G Wilson; Lisa R Yanek; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium; TOPMed Lipids Working Group; Benjamin M Neale; Shamil R Sunyaev; Gonçalo R Abecasis; Jerome I Rotter; Cristen J Willer; Gina M Peloso; Pradeep Natarajan; Xihong Lin

doi:10.1038/s41588-020-0676-4

Dynamic incorporation of multiple in silico functional annotations empowers rare variant association analysis of large whole-genome sequencing studies at scale

Nat Genet. 2020 Sep;52(9):969-983. doi: 10.1038/s41588-020-0676-4. Epub 2020 Aug 24.

Authors

Xihao Li^#¹, Zilin Li^#¹, Hufeng Zhou¹, Sheila M Gaynor¹, Yaowu Liu², Han Chen^{3

4}, Ryan Sun⁵, Rounak Dey¹, Donna K Arnett⁶, Stella Aslibekyan⁷, Christie M Ballantyne⁸, Lawrence F Bielak⁹, John Blangero¹⁰, Eric Boerwinkle^{3

11}, Donald W Bowden¹², Jai G Broome¹³, Matthew P Conomos¹⁴, Adolfo Correa¹⁵, L Adrienne Cupples^{16

17}, Joanne E Curran¹⁰, Barry I Freedman¹⁸, Xiuqing Guo¹⁹, George Hindy²⁰, Marguerite R Irvin⁷, Sharon L R Kardia⁹, Sekar Kathiresan^{21

22

23}, Alyna T Khan¹⁴, Charles L Kooperberg²⁴, Cathy C Laurie¹⁴, X Shirley Liu^{25

26}, Michael C Mahaney¹⁰, Ani W Manichaikul²⁷, Lisa W Martin²⁸, Rasika A Mathias²⁹, Stephen T McGarvey³⁰, Braxton D Mitchell^{31

32}, May E Montasser³³, Jill E Moore³⁴, Alanna C Morrison³, Jeffrey R O'Connell³¹, Nicholette D Palmer¹², Akhil Pampana^{35

36}, Juan M Peralta¹⁰, Patricia A Peyser⁹, Bruce M Psaty^{37

38}, Susan Redline^{39

40

41}, Kenneth M Rice¹⁴, Stephen S Rich²⁷, Jennifer A Smith^{9

42}, Hemant K Tiwari⁴³, Michael Y Tsai⁴⁴, Ramachandran S Vasan^{17

45}, Fei Fei Wang¹⁴, Daniel E Weeks⁴⁶, Zhiping Weng³⁴, James G Wilson^{47

48}, Lisa R Yanek²⁹; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium; TOPMed Lipids Working Group; Benjamin M Neale^{35

49

50}, Shamil R Sunyaev^{35

51

52}, Gonçalo R Abecasis^{53

54}, Jerome I Rotter¹⁹, Cristen J Willer^{55

56

57}, Gina M Peloso¹⁶, Pradeep Natarajan^{23

35

36}, Xihong Lin^{58

59

60}

Collaborators

Namiko Abe, Gonçalo R Abecasis, Francois Aguet, Christine Albert, Laura Almasy, Alvaro Alonso, Seth Ament, Peter Anderson, Pramod Anugu, Deborah Applebaum-Bowden, Kristin Ardlie, 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, Lucas Barwick, Terri Beaty, Gerald Beck, Diane Becker, Lewis Becker, Rebecca Beer, Amber Beitelshees, Emelia Benjamin, Takis Benos, Marcos Bezerra, Lawrence F Bielak, Joshua Bis, Thomas Blackwell, John Blangero, Eric Boerwinkle, Donald W Bowden, Russell Bowler, Jennifer Brody, Ulrich Broeckel, Jai G Broome, Karen Bunting, Esteban Burchard, Carlos Bustamante, Erin Buth, Brian Cade, Jonathan Cardwell, Vincent Carey, Cara Carty, Richard Casaburi, 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, Lee-Ming Chuang, Mina Chung, Ren-Hua Chung, Clary Clish, Suzy Comhair, Matthew P Conomos, Elaine Cornell, Adolfo Correa, Carolyn Crandall, James Crapo, L Adrienne Cupples, Joanne E Curran, Jeffrey Curtis, Brian Custer, Coleen Damcott, Dawood Darbar, Sayantan Das, Sean David, Colleen Davis, Michelle Daya, Mariza de Andrade, Lisa de las Fuentes, Michael DeBaun, Ranjan Deka, Dawn DeMeo, Scott Devine, Qing Duan, Ravi Duggirala, Jon Peter Durda, Susan Dutcher, Charles Eaton, Lynette Ekunwe, Adel El Boueiz, Patrick Ellinor, Leslie Emery, Serpil Erzurum, Charles Farber, Tasha 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, Bruce Gelb, Xiaoqi Priscilla Geng, Mark Geraci, Soren Germer, Robert Gerszten, Auyon Ghosh, Richard Gibbs, Chris Gignoux, Mark Gladwin, David Glahn, Stephanie Gogarten, Da-Wei Gong, Harald Goring, Sharon Graw, Daniel Grine, C Charles Gu, Yue Guan, Xiuqing Guo, Namrata Gupta, Jeff Haessler, Michael Hall, Daniel Harris, Nicola L Hawley, Jiang He, Susan Heckbert, Ryan Hernandez, David Herrington, Craig Hersh, Bertha Hidalgo, James Hixson, Brian Hobbs, John Hokanson, Elliott Hong, Karin Hoth, Chao Agnes Hsiung, Yi-Jen Hung, Haley Huston, Chii Min Hwu, Marguerite R Irvin, Rebecca Jackson, Deepti Jain, Cashell Jaquish, Min A Jhun, Jill Johnsen, Andrew Johnson, Craig Johnson, Rich Johnston, Kimberly Jones, Hyun Min Kang, Robert Kaplan, Sharon L R Kardia, Sekar Kathiresan, Shannon Kelly, Eimear Kenny, Michael Kessler, Alyna T Khan, Wonji Kim, Greg Kinney, Barbara Konkle, Charles L Kooperberg, Holly Kramer, Christoph Lange, Ethan Lange, Leslie Lange, Cathy C Laurie, Cecelia Laurie, Meryl LeBoff, Jiwon Lee, Seunggeun Shawn Lee, Wen-Jane Lee, Jonathon LeFaive, David Levine, Dan Levy, Joshua Lewis, Xiaohui Li, Yun Li, Henry Lin, Honghuang Lin, Keng Han Lin, Xihong Lin, Simin Liu, Yongmei Liu, Yu Liu, Ruth J F Loos, Steven Lubitz, Kathryn Lunetta, James Luo, Michael C Mahaney, Barry Make, Ani W Manichaikul, JoAnn Manson, Lauren Margolin, Lisa W Martin, Susan Mathai, Rasika A Mathias, Susanne May, Patrick McArdle, Merry-Lynn McDonald, Sean McFarland, Stephen T McGarvey, Daniel McGoldrick, Caitlin McHugh, Hao Mei, Luisa Mestroni, Deborah A Meyers, Julie Mikulla, Nancy Min, Mollie Minear, Ryan L Minster, Braxton D Mitchell, Matt Moll, May E Montasser, Courtney Montgomery, Arden Moscati, Solomon Musani, Stanford Mwasongwe, Josyf C Mychaleckyj, Girish Nadkarni, Rakhi Naik, Take Naseri, Pradeep Natarajan, Sergei Nekhai, Sarah C Nelson, Bonnie Neltner, Deborah Nickerson, Kari North, Jeffrey R O'Connell, Tim O'Connor, Heather Ochs-Balcom, David Paik, Nicholette D Palmer, James Pankow, George Papanicolaou, Afshin Parsa, Juan M Peralta, Marco Perez, James Perry, Ulrike Peters, Patricia A Peyser, Lawrence S Phillips, Toni Pollin, Wendy Post, Julia Powers Becker, Meher Preethi Boorgula, Michael Preuss, Bruce M Psaty, Pankaj Qasba, Dandi Qiao, Zhaohui Qin, Nicholas Rafaels, Laura Raffield, Ramachandran S Vasan, D C Rao, Laura Rasmussen-Torvik, Aakrosh Ratan, Susan Redline, Robert Reed, Elizabeth Regan, Alex Reiner, Muagututi'a Sefuiva Reupena, Kenneth M Rice, Stephen S Rich, Dan Roden, Carolina Roselli, Jerome I Rotter, Ingo Ruczinski, Pamela Russell, Sarah Ruuska, Kathleen Ryan, Ester Cerdeira Sabino, Danish Saleheen, Shabnam Salimi, Steven Salzberg, Kevin Sandow, Vijay G Sankaran, Christopher Scheller, Ellen Schmidt, Karen Schwander, David Schwartz, Frank Sciurba, Christine Seidman, Jonathan Seidman, Vivien Sheehan, Stephanie L Sherman, Amol Shetty, Aniket Shetty, Wayne Hui-Heng Sheu, M Benjamin Shoemaker, Brian Silver, Edwin Silverman, Jennifer A 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, Carole Sztalryd, Daniel Taliun, Hua Tang, Margaret Taub, Kent D Taylor, Matthew Taylor, Simeon Taylor, Marilyn Telen, Timothy A Thornton, Machiko Threlkeld, Lesley Tinker, David Tirschwell, Sarah Tishkoff, Hemant K Tiwari, Catherine Tong, Russell Tracy, Michael Y Tsai, Dhananjay Vaidya, David Van Den Berg, Peter VandeHaar, Scott Vrieze, Tarik Walker, Robert Wallace, Avram Walts, Fei Fei Wang, Heming Wang, Karol Watson, Daniel E Weeks, Bruce Weir, Scott Weiss, Lu-Chen Weng, Jennifer Wessel, Cristen J Willer, Kayleen Williams, L Keoki Williams, Carla Wilson, James G Wilson, Quenna Wong, Joseph Wu, Huichun Xu, Lisa R Yanek, Ivana Yang, Rongze Yang, Norann Zaghloul, Maryam Zekavat, Yingze Zhang, Snow Xueyan Zhao, Wei Zhao, Degui Zhi, Xiang Zhou, Xiaofeng Zhu, Michael Zody, Sebastian Zoellner, Moustafa Abdalla, Gonçalo R Abecasis, Donna K Arnett, Stella Aslibekyan, Tim Assimes, Elizabeth Atkinson, Christie M Ballantyne, Amber Beitelshees, Lawrence F Bielak, Joshua Bis, Corneliu Bodea, Eric Boerwinkle, Donald W Bowden, Jennifer Brody, Brian Cade, Jenna Carlson, I-Shou Chang, Yii-Der Ida Chen, Sung Chun, Ren-Hua Chung, Matthew P Conomos, Adolfo Correa, L Adrienne Cupples, Coleen Damcott, Paul de Vries, Ron Do, Amanda Elliott, Mao Fu, Andrea Ganna, Da-Wei Gong, Sarah Graham, Mary Haas, Bernhard Haring, Jiang He, Susan Heckbert, Blanca Himes, James Hixson, Marguerite R Irvin, Deepti Jain, Gail Jarvik, Min A Jhun, Jicai Jiang, Goo Jun, Rita Kalyani, Sharon L R Kardia, Sekar Kathiresan, Amit Khera, Derek Klarin, Charles L Kooperberg, Brian Kral, Leslie Lange, Cathy C Laurie, Cecelia Laurie, Rozenn Lemaitre, Zilin Li, Xihao Li, Xihong Lin, Michael C Mahaney, Ani W Manichaikul, Lisa W Martin, Rasika A Mathias, Ravi Mathur, Stephen T McGarvey, Caitlin McHugh, John McLenithan, Julie Mikulla, Braxton D Mitchell, May E Montasser, Andrew Moran, Alanna C Morrison, Tetsushi Nakao, Pradeep Natarajan, Deborah Nickerson, Kari North, Jeffrey R O'Connell, Christopher O'Donnell, Nicholette D Palmer, Akhil Pampana, Aniruddh Patel, Gina M Peloso, James Perry, Ulrike Peters, Patricia A Peyser, James Pirruccello, Toni Pollin, Michael Preuss, Bruce M Psaty, D C Rao, Susan Redline, Robert Reed, Alex Reiner, Stephen S Rich, Samantha Rosenthal, Jerome I Rotter, Jenny Schoenberg, Margaret Sunitha Selvaraj, Wayne Hui-Heng Sheu, Jennifer A Smith, Tamar Sofer, Adrienne M Stilp, Shamil R Sunyaev, Ida Surakka, Carole Sztalryd, Hua Tang, Kent D Taylor, Michael Y Tsai, Md Mesbah Uddin, Sarah Urbut, Marie Verbanck, Ann Von Holle, Heming Wang, Fei Fei Wang, Kerri Wiggins, Cristen J Willer, James G Wilson, Brooke Wolford, Huichun Xu, Lisa R Yanek, Norann Zaghloul, Maryam Zekavat, Jingwen Zhang

Affiliations

¹ Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
² School of Statistics, Southwestern University of Finance and Economics, Chengdu, China.
³ 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.
⁴ Center for Precision Health, School of Public Health and School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, USA.
⁵ Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁶ College of Public Health, University of Kentucky, Lexington, KY, USA.
⁷ Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA.
⁸ Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
⁹ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
¹⁰ Department of Human Genetics and South Texas Diabetes and Obesity Institute, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, USA.
¹¹ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
¹² Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
¹³ Division of Medical Genetics, University of Washington, Seattle, WA, USA.
¹⁴ Department of Biostatistics, University of Washington, Seattle, WA, USA.
¹⁵ Jackson Heart Study, Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
¹⁶ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
¹⁷ Framingham Heart Study, National Heart, Lung, and Blood Institute and Boston University, Framingham, MA, USA.
¹⁸ Department of Internal Medicine, Nephrology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
¹⁹ 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.
²⁰ Department of Population Medicine, Qatar University College of Medicine, QU Health, Doha, Qatar.
²¹ Verve Therapeutics, Cambridge, MA, USA.
²² Cardiology Division, Massachusetts General Hospital, Boston, MA, USA.
²³ Department of Medicine, Harvard Medical School, Boston, MA, USA.
²⁴ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
²⁵ Department of Data Sciences, Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, MA, USA.
²⁶ Department of Statistics, Harvard University, Cambridge, MA, USA.
²⁷ Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
²⁸ Division of Cardiology, George Washington School of Medicine and Health Sciences, Washington, DC, USA.
²⁹ GeneSTAR Research Program, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³⁰ Department of Epidemiology, International Health Institute, Department of Anthropology, Brown University, Providence, RI, USA.
³¹ Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
³² Geriatrics Research and Education Clinical Center, Baltimore VA Medical Center, Baltimore, MD, USA.
³³ Division of Endocrinology, Diabetes, and Nutrition, Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
³⁴ Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA, USA.
³⁵ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
³⁶ Center for Genomic Medicine and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
³⁷ Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, WA, USA.
³⁸ Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
³⁹ Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, USA.
⁴⁰ Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA.
⁴¹ Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
⁴² Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA.
⁴³ Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA.
⁴⁴ Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
⁴⁵ Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
⁴⁶ Department of Human Genetics and Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA.
⁴⁷ Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.
⁴⁸ Division of Cardiology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
⁴⁹ Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
⁵⁰ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
⁵¹ Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
⁵² Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
⁵³ Regeneron Pharmaceuticals, Tarrytown, NY, USA.
⁵⁴ Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
⁵⁵ Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
⁵⁶ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
⁵⁷ Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
⁵⁸ Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA. [email protected].
⁵⁹ Department of Statistics, Harvard University, Cambridge, MA, USA. [email protected].
⁶⁰ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA. [email protected].

^# Contributed equally.

Abstract

Large-scale whole-genome sequencing studies have enabled the analysis of rare variants (RVs) associated with complex phenotypes. Commonly used RV association tests have limited scope to leverage variant functions. We propose STAAR (variant-set test for association using annotation information), a scalable and powerful RV association test method that effectively incorporates both variant categories and multiple complementary annotations using a dynamic weighting scheme. For the latter, we introduce 'annotation principal components', multidimensional summaries of in silico variant annotations. STAAR accounts for population structure and relatedness and is scalable for analyzing very large cohort and biobank whole-genome sequencing studies of continuous and dichotomous traits. We applied STAAR to identify RVs associated with four lipid traits in 12,316 discovery and 17,822 replication samples from the Trans-Omics for Precision Medicine Program. We discovered and replicated new RV associations, including disruptive missense RVs of NPC1L1 and an intergenic region near APOC1P1 associated with low-density lipoprotein cholesterol.

Publication types

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

MeSH terms

Cholesterol, LDL / genetics
Computer Simulation
Genetic Predisposition to Disease / genetics*
Genetic Variation / genetics*
Genome / genetics*
Genome-Wide Association Study / methods
Humans
Models, Genetic
Molecular Sequence Annotation / methods
Phenotype
Whole Genome Sequencing / methods

Substances

Cholesterol, LDL

Abstract

Publication types

MeSH terms

Substances

Grants and funding