Whole Genome Sequencing Identifies CRISPLD2 as a Lung Function Gene in Children With Asthma

National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine (TOPMed) Consortium

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Background: Asthma is a common respiratory disorder with a highly heterogeneous nature that remains poorly understood. The objective was to use whole genome sequencing (WGS) data to identify regions of common genetic variation contributing to lung function in individuals with a diagnosis of asthma. Methods: WGS data were generated for 1,053 individuals from trios and extended pedigrees participating in the family-based Genetic Epidemiology of Asthma in Costa Rica study. Asthma affection status was defined through a physician's diagnosis of asthma, and most participants with asthma also had airway hyperresponsiveness (AHR) to methacholine. Family-based association tests for single variants were performed to assess the associations with lung function phenotypes. Results: A genome-wide significant association was identified between baseline FEV1/FVC ratio and a single-nucleotide polymorphism in the top hit cysteine-rich secretory protein LCCL domain-containing 2 (CRISPLD2) (rs12051168; P = 3.6 × 10−8 in the unadjusted model) that retained suggestive significance in the covariate-adjusted model (P = 5.6 × 10−6). Rs12051168 was also nominally associated with other related phenotypes: baseline FEV1 (P = 3.3 × 10−3), postbronchodilator (PB) FEV1 (7.3 × 10−3), and PB FEV1/FVC ratio (P = 2.7 × 10−3). The identified baseline FEV1/FVC ratio and rs12051168 association was meta-analyzed and replicated in three independent cohorts in which most participants with asthma also had confirmed AHR (combined weighted z-score P =.015) but not in cohorts without information about AHR. Conclusions: These findings suggest that using specific asthma characteristics, such as AHR, can help identify more genetically homogeneous asthma subgroups with genotype-phenotype associations that may not be observed in all children with asthma. CRISPLD2 also may be important for baseline lung function in individuals with asthma who also may have AHR.

Original languageEnglish (US)
Pages (from-to)1068-1079
Number of pages12
JournalCHEST
Volume156
Issue number6
DOIs
StatePublished - Dec 2019

Bibliographical note

Funding Information:
Author contributions: P. K. takes full responsibility for this manuscript and had the final responsibility to submit it for publication. P. K. and J. H. take responsibility for the integrity and accuracy of the data analysis and had full access to the data. J. C.C. and S. T. W. conceived and designed the initial Costa Rican study. P. K., J. H., B. L. C., M. H. C., D. Q. analyzed the data. P. K., T. S. A., K. C. B., E. G. B., C. E., D.H., J. C. C., M. D., A. M. L., H. G., L. K. W., E.F., A. C. Y. M., L. A., M. E. S. Q., M. M. C., E.A. P., G. C., K. B., and H. B. performed replication in their cohorts and assisted understanding of the data. C. L. advised and provided the statistical supervision. P. K., J.H., B. L. C., and J. A. L. S. wrote the manuscript. R. S. K., S. H. C., Y. V. V., M. H. and B. A. R. contributed to writing and critical reviewing of the manuscript. All authors reviewed and approved of the final manuscript. We thank all the participants, investigators and staff without whom this work could not have been accomplished. Financial/nonfinancial disclosures: The authors have reported to CHEST the following: M. H. C. has received consulting fees from Genentech and grant funding from GlaxoSmithKline. J. C. C. has received research materials from GlaxoSmithKline and Merck (inhaled steroids) and Pharmavite (vitamin D and placebo capsules) to provide medications free of cost to participants in studies funded by the National Institutes of Health, unrelated to the current work. L. A. has participated in speaking activities and symposia for Abbott Laboratories, AstraZeneca, GlaxoSmithKline, Sandoz, and Sanofi Pasteur. M. E. S. Q. has participated in speaking activities for AstraZeneca. B. A. R. has received royalties from UpToDate, Inc., as a section editor for Genetics , and has received honoraria for serving on the advisory boards for Sanofi Genzyme and Teva Pharmaceuticals but has no conflicts of interest directly related to this work. J. A. L. S. has been a consultant to Metabolon, Inc. None declared (P. K., J. H., B. L. C., T. S. A., D. Q., R. S. K., S. H. C., Y. V. V., M. H., K. C. B., E. G. B., C. E., D. H., M. D., A. M. L., H. G., L. K. W., E. F., A. C. Y. M., M. M. C., E. A. P., G. C., K. B., H. B., C. L., S. T. W.). Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript. *National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine (TOPMed) Consortium Collaborators: Namiko Abe, New York Genome Center; Goncalo Abecasis, University of Michigan; Christine Albert, Massachusetts General Hospital; Nicholette (Nichole) Palmer Allred, Wake Forest Baptist Health; Laura Almasy, Children's Hospital of Philadelphia, University of Pennsylvania; Alvaro Alonso, Emory University; Seth Ament, University of Maryland; Peter Anderson, University of Washington; Pramod Anugu, University of Mississippi; Deborah Applebaum-Bowden, National Institutes of Health; Dan Arking, Johns Hopkins University; Donna K. Arnett, University of Kentucky; Allison Ashley-Koch, Duke University; Stella Aslibekyan, University of Alabama; Tim Assimes, Stanford University; Paul Auer, University of Wisconsin Milwaukee; Dimitrios Avramopoulos, Johns Hopkins University; John Barnard, Cleveland Clinic; Kathleen Barnes, University of Colorado at Denver; R. Graham Barr, Columbia University; Emily Barron-Casella, Johns Hopkins University; Terri Beaty, Johns Hopkins University; Diane Becker, Johns Hopkins University; Lewis Becker, Johns Hopkins University; Rebecca Beer, National Heart, Lung, and Blood Institute, National Institutes of Health; Ferdouse Begum, Johns Hopkins University; Amber Beitelshees, University of Maryland; Emelia Benjamin, Boston University, Massachusetts General Hospital; Marcos Bezerra, Fundação de Hematologia e Hemoterapia de Pernambuco—Hemope; Larry Bielak, University of Michigan; Joshua Bis, University of Washington; Thomas Blackwell, University of Michigan; John Blangero, University of Texas Rio Grande Valley School of Medicine; Eric Boerwinkle, University of Texas Health at Houston; Ingrid Borecki, University of Washington; Russell Bowler, National Jewish Health; Jennifer Brody, University of Washington; Ulrich Broeckel, Medical College of Wisconsin; Jai Broome, University of Washington; Karen Bunting, New York Genome Center; Esteban Burchard, University of California, San Francisco; Jonathan Cardwell, University of Colorado at Denver; Cara Carty, Women's Health Initiative; Richard Casaburi, University of California, Los Angeles; James Casella, Johns Hopkins University; Mark Chaffin, The Broad Institute; Christy Chang, University of Maryland; Daniel Chasman, Brigham and Women's Hospital; Sameer Chavan, University of Colorado at Denver; Bo-Juen Chen, New York Genome Center; Wei-Min Chen, University of Virginia; Yii-Der Ida Chen, Los Angeles Biomedical Research Institute; Michael H. Cho, Brigham and Women's Hospital; Seung Hoan Choi, The Broad Institute; Lee-Ming Chuang, National Taiwan University; Mina Chung, Cleveland Clinic; Elaine Cornell, University of Vermont; Adolfo Correa, University of Mississippi; Carolyn Crandall, University of California, Los Angeles; James Crapo, National Jewish Health; L. Adrienne Cupples, Boston University; Joanne Curran, University of Texas Rio Grande Valley School of Medicine; Jeffrey Curtis, University of Michigan; Brian Custer, Blood Systems Research Institute UCSF; Coleen Damcott, University of Maryland; Dawood Darbar, University of Illinois at Chicago; Sayantan Das, University of Michigan; Sean David, Stanford University; Colleen Davis, University of Washington; Michelle Daya, University of Colorado at Denver; Mariza de Andrade, Mayo Clinic; Michael DeBaun, Vanderbilt University; Ranjan Deka, University of Cincinnati; Dawn DeMeo, Brigham and Women's Hospital; Scott Devine, University of Maryland; Ron Do, Icahn School of Medicine at Mount Sinai; Qing Duan, University of North Carolina; Ravi Duggirala, University of Texas Rio Grande Valley School of Medicine; Peter Durda, University of Vermont; Susan Dutcher, Washington University in St. Louis; Charles Eaton, Brown University; Lynette Ekunwe, University of Mississippi; Patrick Ellinor, Massachusetts General Hospital; Leslie Emery, University of Washington; Charles Farber, University of Virginia; Leanna Farnam, Brigham and Women's Hospital; Tasha Fingerlin, National Jewish Health; Matthew Flickinger, University of Michigan; Myriam Fornage, University of Texas Health at Houston; Nora Franceschini, University of North Carolina; Mao Fu, University of Maryland; Stephanie M. Fullerton, University of Washington; Lucinda Fulton, Washington University in St. Louis; Stacey Gabriel, The Broad Institute; Weiniu Gan, National Heart, Lung, and Blood Institute, National Institutes of Health; Yan Gao, University of Mississippi; Margery Gass, Fred Hutchinson Cancer Research Center; Bruce Gelb, Icahn School of Medicine at Mount Sinai; Xiaoqi (Priscilla) Geng, University of Michigan; Soren Germer, New York Genome Center; Chris Gignoux, Stanford University; Mark Gladwin, University of Pittsburgh; David Glahn, Yale University; Stephanie Gogarten, University of Washington; Da-Wei Gong, University of Maryland; Harald Goring, University of Texas Rio Grande Valley School of Medicine; C. Charles Gu, Washington University in St. Louis; Yue Guan, University of Maryland; Xiuqing Guo, Los Angeles Biomedical Research Institute; Jeff Haessler, Fred Hutchinson Cancer Research Center, Women's Health Initiative; Michael Hall, University of Mississippi; Daniel Harris, University of Maryland; Nicola Hawley, Yale University; Jiang He, Tulane University; Ben Heavner, University of Washington; Susan Heckbert, University of Washington; Ryan Hernandez, University of California, San Francisco; David Herrington, Wake Forest Baptist Health; Craig Hersh, Brigham and Women's Hospital; Bertha Hidalgo, University of Alabama; James Hixson, University of Texas Health at Houston; John Hokanson, University of Colorado at Denver; Kramer Holly, Loyola University; Elliott Hong, University of Maryland; Karin Hoth, University of Iowa; Chao (Agnes) Hsiung, National Health Research Institute Taiwan; Haley Huston, Blood Works Northwest; Chii Min Hwu, Taichung Veterans General Hospital Taiwan; Marguerite Ryan Irvin, University of Alabama; Rebecca Jackson, Ohio State University Wexner Medical Center; Deepti Jain, University of Washington; Cashell Jaquish, National Heart, Lung, and Blood Institute, National Institutes of Health; Min A. Jhun, University of Michigan; Jill Johnsen, Blood Works Northwest, University of Washington; Andrew Johnson, National Heart, Lung, and Blood Institute, National Institutes of Health; Craig Johnson, University of Washington; Rich Johnston, Emory University; Kimberly Jones, Johns Hopkins University; Priyadarshini Kachroo, Brigham and Women's Hospital; Hyun Min Kang, University of Michigan; Robert Kaplan, Albert Einstein College of Medicine; Sharon Kardia, University of Michigan; Sekar Kathiresan, The Broad Institute; Laura Kaufman, Brigham and Women's Hospital; Shannon Kelly, Vitalant; Eimear Kenny, Icahn School of Medicine at Mount Sinai; Michael Kessler, University of Maryland; Alyna Khan, University of Washington; Greg Kinney, University of Colorado at Denver; Barbara Konkle, Blood Works Northwest; Charles Kooperberg, Fred Hutchinson Cancer Research Center; Stephanie Krauter, University of Washington; Christoph Lange, Harvard School of Public Health; Ethan Lange, University of Colorado at Denver; Leslie Lange, University of Colorado at Denver; Cathy Laurie, University of Washington; Cecelia Laurie, University of Washington; Meryl LeBoff, Brigham and Women's Hospital; Seunggeun Shawn Lee, University of Michigan; Wen-Jane Lee, Taichung Veterans General Hospital Taiwan; Jonathon LeFaive, University of Michigan; David Levine, University of Washington; Dan Levy, National Heart, Lung, and Blood Institute, National Institutes of Health; Joshua Lewis, University of Maryland; Yun Li, University of North Carolina; Honghuang Lin, Boston University; Keng Han Lin, University of Michigan; Simin Liu, Brown University, Women's Health Initiative; Yongmei Liu, Wake Forest Baptist Health; Ruth Loos, Icahn School of Medicine at Mount Sinai; Steven Lubitz, Massachusetts General Hospital; Kathryn Lunetta, Boston University; James Luo, National Heart, Lung, and Blood Institute, National Institutes of Health; Michael Mahaney, University of Texas Rio Grande Valley School of Medicine; Barry Make, Johns Hopkins University; Ani Manichaikul, University of Virginia; JoAnn Manson, Brigham and Women's Hospital; Lauren Margolin, The Broad Institute; Lisa Martin, George Washington University; Susan Mathai, University of Colorado at Denver; Rasika Mathias, Johns Hopkins University; Patrick McArdle, University of Maryland; Merry-Lynn McDonald, University of Alabama; Sean McFarland, Harvard University; Stephen McGarvey, Brown University; Hao Mei, University of Mississippi; Deborah A. Meyers, University of Arizona; Julie Mikulla, National Heart, Lung, and Blood Institute, National Institutes of Health; Nancy Min, University of Mississippi; Mollie Minear, National Heart, Lung, and Blood Institute, National Institutes of Health; Ryan L. Minster, University of Pittsburgh; Braxton Mitchell, University of Maryland; May E. Montasser, University of Maryland; Solomon Musani, University of Mississippi; Stanford Mwasongwe, University of Mississippi; Josyf C. Mychaleckyj, University of Virginia; Girish Nadkarni, Icahn School of Medicine at Mount Sinai; Rakhi Naik, Johns Hopkins University; Pradeep Natarajan, The Broad Institute, Harvard University, Massachusetts General Hospital; Sergei Nekhai, Howard University; Deborah Nickerson, University of Washington; Kari North, University of North Carolina; Jeff O'Connell, University of Maryland; Tim O'Connor, University of Maryland; Heather Ochs-Balcom, University at Buffalo; James Pankow, University of Minnesota; George Papanicolaou, National Heart, Lung, and Blood Institute, National Institutes of Health; Margaret Parker, Brigham and Women's Hospital; Afshin Parsa, University of Maryland; Sara Penchev, National Jewish Health; Juan Manuel Peralta, University of Texas Rio Grande Valley School of Medicine; Marco Perez, Stanford University; James Perry, University of Maryland; Ulrike Peters, Fred Hutchinson Cancer Research Center, University of Washington; Patricia Peyser, University of Michigan; Lawrence S. Phillips, Emory University; Sam Phillips, University of Washington; Toni Pollin, University of Maryland; Wendy Post, Johns Hopkins University; Julia Powers Becker, University of Colorado at Denver; Meher Preethi Boorgula, University of Colorado at Denver; Michael Preuss, Icahn School of Medicine at Mount Sinai; Dmitry Prokopenko, Harvard University; Bruce Psaty, University of Washington; Pankaj Qasba, National Heart, Lung, and Blood Institute, National Institutes of Health; Dandi Qiao, Brigham and Women's Hospital; Zhaohui Qin, Emory University; Nicholas Rafaels, University of Colorado at Denver; Laura Raffield, University of North Carolina; Vasan Ramachandran, Boston University; D. C. Rao, Washington University in St. Louis; Laura Rasmussen-Torvik, Northwestern University; Aakrosh Ratan, University of Virginia; Susan Redline, Brigham and Women's Hospital; Robert Reed, University of Maryland; Elizabeth Regan, National Jewish Health; Alex Reiner, Fred Hutchinson Cancer Research Center, University of Washington; Ken Rice, University of Washington; Stephen Rich, University of Virginia; Dan Roden, Vanderbilt University; Carolina Roselli, The Broad Institute; Jerome Rotter, Los Angeles Biomedical Research Institute; Ingo Ruczinski, Johns Hopkins University; Pamela Russell, University of Colorado at Denver; Sarah Ruuska, Blood Works Northwest; Kathleen Ryan, University of Maryland; Phuwanat Sakornsakolpat, Brigham and Women's Hospital; Shabnam Salimi, University of Maryland; Steven Salzberg, Johns Hopkins University; Kevin Sandow, Los Angeles Biomedical Research Institute; Vijay Sankaran, Harvard University; Christopher Scheller, University of Michigan; Ellen Schmidt, University of Michigan; Karen Schwander, Washington University in St. Louis; David Schwartz, University of Colorado at Denver; Frank Sciurba, University of Pittsburgh; Christine Seidman, Harvard Medical School; Jonathan Seidman, Harvard Medical School; Vivien Sheehan, Baylor College of Medicine; Amol Shetty, University of Maryland; Aniket Shetty, University of Colorado at Denver; Wayne Hui-Heng Sheu, Taichung Veterans General Hospital Taiwan; M. Benjamin Shoemaker, Vanderbilt University; Brian Silver, UMass Memorial Medical Center; Edwin Silverman, Brigham and Women's Hospital; Jennifer Smith, University of Michigan; Josh Smith, University of Washington; Nicholas Smith, University of Washington; Tanja Smith, New York Genome Center; Sylvia Smoller, Albert Einstein College of Medicine; Beverly Snively, Wake Forest Baptist Health; Tamar Sofer, Brigham and Women's Hospital; Nona Sotoodehnia, University of Washington; Adrienne Stilp, University of Washington; Elizabeth Streeten, University of Maryland; Yun Ju Sung, Washington University in St. Louis; Jessica Su-Lasky, Brigham and Women's Hospital; Jody Sylvia, Brigham and Women's Hospital; Adam Szpiro, University of Washington; Carole Sztalryd, University of Maryland; Daniel Taliun, University of Michigan; Hua Tang, Stanford University; Margaret Taub, Johns Hopkins University; Kent Taylor, Los Angeles Biomedical Research Institute; Simeon Taylor, University of Maryland; Marilyn Telen, Duke University; Timothy A. Thornton, University of Washington; Lesley Tinker, Women's Health Initiative; David Tirschwell, University of Washington; Hemant Tiwari, University of Alabama; Russell Tracy, University of Vermont; Michael Tsai, University of Minnesota; Dhananjay Vaidya, Johns Hopkins University; Peter VandeHaar, University of Michigan; Scott Vrieze, University of Colorado at Boulder, University of Minnesota; Tarik Walker, University of Colorado at Denver; Robert Wallace, University of Iowa; Avram Walts, University of Colorado at Denver; Emily Wan, Brigham and Women's Hospital; Fei Fei Wang, University of Washington; Karol Watson, University of California, Los Angeles; Daniel E. Weeks, University of Pittsburgh; Bruce Weir, University of Washington; Scott Weiss, Brigham and Women's Hospital; Lu-Chen Weng, Massachusetts General Hospital; Cristen Willer, University of Michigan; Kayleen Williams, University of Washington; L. Keoki Williams, Henry Ford Health System; Carla Wilson, Brigham and Women's Hospital; James Wilson, University of Mississippi; Quenna Wong, University of Washington; Huichun Xu, University of Maryland; Lisa Yanek, Johns Hopkins University; Ivana Yang, University of Colorado at Denver; Rongze Yang, University of Maryland; Norann Zaghloul, University of Maryland; Maryam Zekavat, The Broad Institute; Yingze Zhang, University of Pittsburgh; Snow Xueyan Zhao, National Jewish Health; Wei Zhao, University of Michigan; Xiuwen Zheng, University of Washington; Degui Zhi, University of Texas Health at Houston; Xiang Zhou, University of Michigan; Michael Zody, New York Genome Center; Sebastian Zoellner, University of Michigan Other contributions: The National Heart, Lung, and Blood Institute (NHLBI) supported whole genome sequencing (WGS) for the Trans-Omics for Precision Medicine (TOPMed) program. WGS for NHLBI TOPMed: Genes-Environments and Admixture in Latino Americans (GALA II) study (phs#000920) was performed at the New York Genome Center (NYGC) (3R01HL117004-02S3). WGS for NHLBI TOPMed: Study of African Americans, Asthma, Genes and Environments (SAGE) (phs#000921) was performed at NYGC (3R01HL117004-02S3). WGS for NHLBI TOPMed: Genetic Epidemiology of Asthma in Costa Rica study (GACRS) (phs#000988) was performed at the University of Washington Northwest Genomics Center (3R37HL066289-13S1). Centralized read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1). Phenotype harmonization, data management, sample-identity quality control, and general study coordination were provided by the TOPMed Data Coordinating Center (3R01HL-120393-02S1). We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. The authors wish to acknowledge the following GALA II coinvestigators for subject recruitment, sample processing, and quality control: Sandra Salazar, Scott Huntsman, MSc; Lisa Caine; Shannon Thyne, MD; Harold J. Farber, MD, MSPH; Pedro C. Avila, MD; Denise Serebrisky, MD; William Rodriguez-Cintron, MD; Jose R. Rodriguez-Santana, MD; Rajesh Kumar, MD; Luisa N. Borrell, DDS, PhD; Emerita Brigino-Buenaventura, MD; Adam Davis, MA, MPH; Michael A. LeNoir, MD; Kelley Meade, MD; Saunak Sen, PhD; Fred Lurmann, MS; and Harold J. Farber, MD, MSPH. The authors also wish to thank the staff and participants who contributed to GALA II and SAGE. Additional information: The e-Appendix and e-Tables can be found in the Supplemental Materials section of the online article.

Publisher Copyright:
© 2019 American College of Chest Physicians

Keywords

  • airway hyperresponsiveness
  • asthma
  • lung function
  • whole genome sequencing

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