Powerful, scalable and resource-efficient meta-analysis of rare variant associations in large whole genome sequencing studies

Xihao Li, Corbin Quick, Hufeng Zhou, Sheila M. Gaynor, Yaowu Liu, Han Chen, Margaret Sunitha Selvaraj, Ryan Sun, Rounak Dey, Donna K. Arnett, Lawrence F. Bielak, Joshua C. Bis, John Blangero, Eric Boerwinkle, Donald W. Bowden, Jennifer A. Brody, Brian E. Cade, Adolfo Correa, L. Adrienne Cupples, Joanne E. CurranPaul S. de Vries, Ravindranath Duggirala, Barry I. Freedman, Harald H.H. Göring, Xiuqing Guo, Jeffrey Haessler, Rita R. Kalyani, Charles Kooperberg, Brian G. Kral, Leslie A. Lange, Ani Manichaikul, Lisa W. Martin, Stephen T. McGarvey, Braxton D. Mitchell, May E. Montasser, Alanna C. Morrison, Take Naseri, Jeffrey R. O’Connell, Nicholette D. Palmer, Patricia A. Peyser, Bruce M. Psaty, Laura M. Raffield, Susan Redline, Alexander P. Reiner, Muagututi’a Sefuiva Reupena, Kenneth M. Rice, Stephen S. Rich, Colleen M. Sitlani, Jennifer A. Smith, Kent D. Taylor, Ramachandran S. Vasan, Cristen J. Willer, James G. Wilson, Lisa R. Yanek, Wei Zhao, Jerome I. Rotter, Pradeep Natarajan, Gina M. Peloso, Zilin Li, Xihong Lin, Namiko Abe, Gonçalo Abecasis, Francois Aguet, Christine Albert, Laura Almasy, Alvaro Alonso, Seth Ament, Peter Anderson, Pramod Anugu, Deborah Applebaum-Bowden, Kristin Ardlie, Arking Dan Arking, Allison Ashley-Koch, Stella Aslibekyan, 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, Thomas Blackwell, Nathan Blue, Russell Bowler, Ulrich Broeckel, Jai Broome, Deborah Brown, Karen Bunting, Esteban Burchard, Carlos Bustamante, Erin Buth, Jonathan Cardwell, Vincent Carey, Julie Carrier, April Carson, 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, Lee Ming Chuang, Mina Chung, Ren Hua Chung, Clary Clish, Suzy Comhair, Matthew Conomos, Elaine Cornell, Carolyn Crandall, James Crapo, Jeffrey Curtis, Brian Custer, Coleen Damcott, Dawood Darbar, Sean David, Colleen Davis, Michelle Daya, Mariza de Andrade, Lisa de las Fuentes, Michael DeBaun, Ranjan Deka, Dawn DeMeo, Scott Devine, Huyen Dinh, Harsha Doddapaneni, Qing Duan, Shannon Dugan-Perez, Jon Peter Durda, Susan K. Dutcher, Charles Eaton, Lynette Ekunwe, Adel El Boueiz, Patrick Ellinor, Leslie Emery, Serpil Erzurum, Charles Farber, Jesse Farek, 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, Heather Geiger, Bruce Gelb, Mark Geraci, Soren Germer, Robert Gerszten, Auyon Ghosh, Richard Gibbs, Chris Gignoux, Mark Gladwin, David Glahn, Stephanie Gogarten, Da Wei Gong, Sharon Graw, Kathryn J. Gray, Daniel Grine, Colin Gross, C. Charles Gu, Yue Guan, Namrata Gupta, Michael Hall, Yi Han, Patrick Hanly, Daniel Harris, Nicola L. Hawley, Jiang He, Heavner Ben Heavner, Susan Heckbert, Ryan Hernandez, David Herrington, Craig Hersh, Bertha Hidalgo, James Hixson, Brian Hobbs, John Hokanson, Elliott Hong, Karin Hoth, Chao Hsiung, Jianhong Hu, Yi Jen Hung, Haley Huston, Chii Min Hwu, Marguerite Ryan Irvin, Rebecca Jackson, Deepti Jain, Cashell Jaquish, Jill Johnsen, Andrew Johnson, Craig Johnson, Rich Johnston, Kimberly Jones, Hyun Min Kang, Robert Kaplan, Sharon Kardia, 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, Xiaohui Li, Yun Li, Henry Lin, Honghuang Lin, Simin Liu, Yongmei Liu, Yu Liu, Ruth J.F. Loos, Steven Lubitz, Kathryn Lunetta, James Luo, Ulysses Magalang, Michael Mahaney, Barry Make, Alisa Manning, Jo Ann Manson, Melissa Marton, Susan Mathai, Rasika Mathias, 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, Deborah Nickerson, Osuji Nkechinyere, Kari North, 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, Mahitha Rajendran, D. C. Rao, Laura Rasmussen-Torvik, Aakrosh Ratan, Robert Reed, Catherine Reeves, Elizabeth Regan, Rebecca Robillard, Nicolas Robine, Roden 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, Russell Tracy, Michael Tsai, 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, Lara Winterkorn, Quenna Wong, Joseph Wu, Huichun Xu, Ivana Yang, Ketian Yu, Seyedeh Maryam Zekavat, Yingze Zhang, Snow Xueyan Zhao, Xiaofeng Zhu, Elad Ziv, Michael Zody, Sebastian Zoellner

Producción científica: Articlerevisión exhaustiva

12 Citas (Scopus)

Resumen

Meta-analysis of whole genome sequencing/whole exome sequencing (WGS/WES) studies provides an attractive solution to the problem of collecting large sample sizes for discovering rare variants associated with complex phenotypes. Existing rare variant meta-analysis approaches are not scalable to biobank-scale WGS data. Here we present MetaSTAAR, a powerful and resource-efficient rare variant meta-analysis framework for large-scale WGS/WES studies. MetaSTAAR accounts for relatedness and population structure, can analyze both quantitative and dichotomous traits and boosts the power of rare variant tests by incorporating multiple variant functional annotations. Through meta-analysis of four lipid traits in 30,138 ancestrally diverse samples from 14 studies of the Trans Omics for Precision Medicine (TOPMed) Program, we show that MetaSTAAR performs rare variant meta-analysis at scale and produces results comparable to using pooled data. Additionally, we identified several conditionally significant rare variant associations with lipid traits. We further demonstrate that MetaSTAAR is scalable to biobank-scale cohorts through meta-analysis of TOPMed WGS data and UK Biobank WES data of ~200,000 samples.

Idioma originalEnglish (US)
Páginas (desde-hasta)154-164
Número de páginas11
PublicaciónNature Genetics
Volumen55
N.º1
DOI
EstadoPublished - ene 2023

ASJC Scopus subject areas

  • Genetics

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