A framework for detecting noncoding rare-variant associations of large-scale whole-genome sequencing studies

• DOI: 10.1038/s41592-022-01640-x
• Publication Date: 2022-10-27T16:06:35Z
• Authors: Zilin Li; Xihao Li; Hufeng Zhou; Sheila M. Gaynor; Margaret Sunitha ...; Theodore Arapoglou; Corbin Quick; Yaowu Liu; Han Chen; Ryan Sun; Rounak Dey; Donna K. Arnett; Paul L. Auer; Lawrence F. Bielak; Joshua C. Bis; Thomas W. Blackwell; John Blangero; Eric Boerwinkle; Donald W. Bowden; Jennifer A. Brody; Brian E. Cade; Matthew P. Conomos; Adolfo Correa; L. Adrienne Cupples; Joanne E. Curran; Paul S. de Vries; Ravindranath Dugg...; Nora Franceschini; Barry I. Freedman; Harald H. H. Göring; Xiuqing Guo; Rita R. Kalyani; Charles Kooperberg; Brian G. Kral; Leslie A. Lange; Bridget M. Lin; Ani Manichaikul; Alisa K. Manning; Lisa W. Martin; Rasika A. Mathias; James B. Meigs; 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 Sefui...; Kenneth M. Rice; Stephen S. Rich; Jennifer A. Smith; Kent D. Taylor; Margaret A. Taub; Ramachandran S. V...; Daniel E. Weeks; James G. Wilson; Lisa R. Yanek; Wei Zhao; ; Namiko Abe; Gonçalo Abecasis; Francois Aguet; Christine Albert; Laura Almasy; Alvaro Alonso; Seth Ament; Peter Anderson; Pramod Anugu; Deborah Applebaum...; Kristin Ardlie; Dan Arking; Allison Ashley-Koch; Stella Aslibekyan; Tim Assimes; Dimitrios Avramop...; Najib Ayas; Adithya Balasubra...; 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; 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; 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; Chris Frazar; Mao Fu; Stephanie M. Full...; 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; 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 I...; 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; JoAnn Manson; Melissa Marton; Susan Mathai; Susanne May; Patrick McArdle; Merry-Lynn McDonald; Sean McFarland; Daniel McGoldrick; Caitlin McHugh; Becky McNeil; Hao Mei; 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 Boo...; Michael Preuss; Pankaj Qasba; Dandi Qiao; Zhaohui Qin; Nicholas Rafaels; Mahitha Rajendran; D. C. Rao; Laura Rasmussen-T...; Aakrosh Ratan; Robert Reed; Catherine Reeves; Elizabeth Regan; Rebecca Robillard; Nicolas Robine; Dan Roden; Carolina Roselli; Ingo Ruczinski; Alexi Runnels; Pamela Russell; Sarah Ruuska; Kathleen Ryan; Ester Cerdeira Sa...; 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 Shoem...; 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; 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 Ze...; Yingze Zhang; Snow Xueyan Zhao; Xiaofeng Zhu; Elad Ziv; Michael Zody; Sebastian Zoellner; ; Elizabeth Atkinson; Christie Ballantyne; Wei Bao; Romit Bhattacharya; Larry Bielak; Joshua Bis; Corneliu Bodea; Jennifer Brody; Brian Cade; Sarah Calvo; Jenna Carlson; I-Shou Chang; So Mi Cho; Paul de Vries; Ana F. Diallo; Ron Do; Jacqueline Dron; Amanda Elliott; Hilary Finucane; Caitlin Floyd; Andrea Ganna; Dawei Gong; Sarah Graham; Mary Haas; Bernhard Haring; Scott Heemann; Blanca Himes; Gail Jarvik; Jicai Jiang; Roby Joehanes; Paule Valery Joseph; Goo Jun; Rita Kalyani; Masahiro Kanai; Sekar Kathiresan; Amit Khera; Sumeet Khetarpal; Derek Klarin; Satoshi Koyama; Brian Kral; Leslie Lange; Rozenn Lemaitre; Changwei Li; Yingchang Lu; Lisa Martin; Rasika Mathias; Ravi Mathur; Stephen McGarvey; John McLenithan; Amy Miller; Vamsi Mootha; Andrew Moran; Tetsushi Nakao; Jeff O’Connell; Christopher O’Don...; Nicholette Palmer; Kaavya Paruchuri; Aniruddh Patel; Gina Peloso; Mary Pettinger; Patricia Peyser; James Pirruccello; Bruce Psaty; Alex Reiner; Stephen Rich; Samantha Rosenthal; Jerome Rotter; Jennifer Smith; Shamil R. Sunyaev; Ida Surakka; Carole Sztalryd; Mark Trinder; Md Mesbah Uddin; Sarah Urbut; Eric Van Buren; Marie Verbanck; Ann Von Holle; Yuxuan Wang; Kerri Wiggins; John Wilkins; Cristen Willer; James Wilson; Brooke Wolford; Lisa Yanek; Zhi Yu; Norann Zaghloul; Jingwen Zhang; Ying Zhou; Jerome I. Rotter; Cristen J. Willer; Pradeep Natarajan; Gina M. Peloso; Xihong Lin
• Keywords: Genetic Association; Gene Annotation

Large-scale whole-genome sequencing studies have enabled analysis of noncoding rare-variant (RV) associations with complex human diseases and traits. Variant-set analysis is a powerful approach to study RV association. However, existing methods have limited ability in analyzing the noncoding genome. We propose a computationally efficient and robust noncoding RV association detection framework, STAARpipeline, to automatically annotate a whole-genome sequencing study and perform flexible noncoding RV association analysis, including gene-centric analysis and fixed window-based and dynamic window-based non-gene-centric analysis by incorporating variant functional annotations. In gene-centric analysis, STAARpipeline uses STAAR to group noncoding variants based on functional categories of genes and incorporate multiple functional annotations. In non-gene-centric analysis, STAARpipeline uses SCANG-STAAR to incorporate dynamic window sizes and multiple functional annotations. We apply STAARpipeline to identify noncoding RV sets associated with four lipid traits in 21,015 discovery samples from the Trans-Omics for Precision Medicine (TOPMed) program and replicate several of them in an additional 9,123 TOPMed samples. We also analyze five non-lipid TOPMed traits.