Whole-genome association analyses of sleep-disordered breathing phenotypes in the NHLBI TOPMed program

Brian E Cade; Jiwon Lee; Tamar Sofer; Heming Wang; Man Zhang; Han Chen; Sina A Gharib; Daniel J Gottlieb; Xiuqing Guo; Jacqueline M Lane; Jingjing Liang; Xihong Lin; Hao Mei; Sanjay R Patel; Shaun M Purcell; Richa Saxena; Neomi A Shah; Daniel S Evans; Craig L Hanis; David R Hillman; Sutapa Mukherjee; Lyle J Palmer; Katie L Stone; Gregory J Tranah; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium; Gonçalo R Abecasis; Eric A Boerwinkle; Adolfo Correa; L Adrienne Cupples; Robert C Kaplan; Deborah A Nickerson; Kari E North; Bruce M Psaty; Jerome I Rotter; Stephen S Rich; Russell P Tracy; Ramachandran S Vasan; James G Wilson; Xiaofeng Zhu; Susan Redline; TOPMed Sleep Working Group

doi:10.1186/s13073-021-00917-8

Whole-genome association analyses of sleep-disordered breathing phenotypes in the NHLBI TOPMed program

Genome Med. 2021 Aug 26;13(1):136. doi: 10.1186/s13073-021-00917-8.

Authors

Brian E Cade^{1

2

3}, Jiwon Lee⁴, Tamar Sofer^{4

5}, Heming Wang^{4

5

6}, Man Zhang⁷, Han Chen^{8

9}, Sina A Gharib¹⁰, Daniel J Gottlieb^{4

5

11}, Xiuqing Guo¹², Jacqueline M Lane^{4

5

6

13}, Jingjing Liang¹⁴, Xihong Lin¹⁵, Hao Mei¹⁶, Sanjay R Patel¹⁷, Shaun M Purcell^{4

5

6}, Richa Saxena^{4

5

6

13}, Neomi A Shah¹⁸, Daniel S Evans¹⁹, Craig L Hanis⁸, David R Hillman²⁰, Sutapa Mukherjee^{21

22}, Lyle J Palmer²³, Katie L Stone¹⁹, Gregory J Tranah¹⁹; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium; Gonçalo R Abecasis²⁴, Eric A Boerwinkle^{8

25}, Adolfo Correa^{26

27}, L Adrienne Cupples^{28

29}, Robert C Kaplan³⁰, Deborah A Nickerson^{31

32}, Kari E North³³, Bruce M Psaty^{34

35}, Jerome I Rotter¹², Stephen S Rich³⁶, Russell P Tracy³⁷, Ramachandran S Vasan^{29

38

39}, James G Wilson⁴⁰, Xiaofeng Zhu¹⁴, Susan Redline^{4

5

41}; TOPMed Sleep Working Group

Collaborators

Namiko Abe, Goncalo Abecasis, Christine Albert, 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, Donald W Bowden, Russell Bowler, Jennifer Brody, Ulrich Broeckel, Jai Broome, Karen Bunting, Esteban Burchard, Brian Cade, Jonathan Cardwell, Cara Carty, Richard Casaburi, James Casella, Mark Chaffin, 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, Adolfo Correa, Carolyn Crandall, James Crapo, L Adrienne Cupples, 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, Mao Fu, 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, Craig Johnson, Rich Johnston, Kimberly Jones, Hyun Min Kang, Robert Kaplan, Sharon Kardia, Sekar Kathiresan, 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, Jiwon Lee, Seunggeun Shawn Lee, Wen-Jane Lee, Jonathon LeFaive, David Levine, Dan Levy, Joshua Lewis, Yun Li, Honghuang Lin, Keng Han Lin, Xihong Lin, Simin Liu, Yongmei Liu, Ruth Loos, Steven Lubitz, Kathryn Lunetta, James Luo, Michael Mahaney, Barry Make, Ani Manichaikul, Jo Ann 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, Braxton D Mitchell, May E Montasser, Solomon Musani, Stanford Mwasongwe, Josyf C Mychaleckyj, Girish Nadkarni, Rakhi Naik, Take Naseri, Pradeep Natarajan, Sergei Nekhai, Deborah Nickerson, Kari North, Jeff O'Connell, Tim O'Connor, Heather Ochs-Balcom, Nicholette Palmer, James Pankow, George Papanicolaou, Margaret Parker, Afshin Parsa, Sara Penchev, Juan Manuel Peralta, Marco Perez, James Perry, Ulrike Peters, Patricia Peyser, Lawrence S Phillips, Sam Phillips, Toni Pollin, Wendy Post, 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, Muagututi'a Sefuiva Reupena, Ken Rice, Stephen Rich, Dan Roden, Carolina Roselli, Jerome Rotter, Ingo Ruczinski, Pamela Russell, Sarah Ruuska, Kathleen Ryan, Phuwanat Sakornsakolpat, Shabnam Salimi, Steven Salzberg, Kevin Sandow, Vijay Sankaran, Christopher Scheller, Ellen Schmidt, Karen Schwander, David Schwartz, Frank Sciurba, Christine Seidman, Jonathan 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, Jessica Lasky Su, Yun Ju Sung, Jody Sylvia, Adam Szpiro, Carole Sztalryd, Daniel Taliun, Hua Tang, Margaret Taub, Kent D Taylor, Simeon Taylor, Marilyn Telen, Timothy A Thornton, Lesley Tinker, David Tirschwell, Hemant Tiwari, Russell Tracy, Michael Tsai, Dhananjay Vaidya, Peter VandeHaar, Ramachandran S Vasan, Scott Vrieze, Tarik Walker, Robert Wallace, Avram Walts, Emily Wan, Fei Fei Wang, Heming Wang, Karol Watson, Daniel E Weeks, Bruce Weir, Scott Weiss, Lu-Chen Weng, Cristen Willer, Kayleen Williams, L Keoki Williams, Carla Wilson, James Wilson, Quenna Wong, Huichun Xu, Lisa Yanek, Ivana Yang, Rongze Yang, Norann Zaghloul, Maryam Zekavat, Yingze Zhang, Snow Xueyan Zhao, Wei Zhao, Xiuwen Zheng, Degui Zhi, Xiang Zhou, Xiaofeng Zhu, Michael Zody, Sebastian Zoellner, Brian Cade, Han Chen, Sina Gharib, Matthew Goodman, Daniel Gottlieb, Lauren Hale, Kristen Knutson, Diane Lauderdale, Jacqueline Lane, Jiwon Lee, Jingjing Liang, Xihong Lin, Yaowu Liu, Hao Mei, Braxton Mitchell, Debby Ngo, Jeff O'Connell, Heather Ochs-Balcom, Sanjay Patel, Shaun Purcell, Susan Redline, Jessica Rhodes, Richa Saxena, Neomi Shah, Tamar Sofer, Jae Hoon Sul, Shamil Sunyaev, Heming Wang, James Wilson, Man Zhang, Hufeng Zhou, Xiaofeng Zhu

Affiliations

¹ Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, Boston, MA, 02115, USA. [email protected].
² Division of Sleep Medicine, Harvard Medical School, Boston, MA, 02115, USA. [email protected].
³ Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, 02142, USA. [email protected].
⁴ Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, Boston, MA, 02115, USA.
⁵ Division of Sleep Medicine, Harvard Medical School, Boston, MA, 02115, USA.
⁶ Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, 02142, USA.
⁷ Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
⁸ 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, 77030, USA.
⁹ Center for Precision Health, School of Public Health and School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
¹⁰ Computational Medicine Core, Center for Lung Biology, UW Medicine Sleep Center, Division of Pulmonary, Critical Care and Sleep Medicine, University of Washington, Seattle, WA, 98195, USA.
¹¹ VA Boston Healthcare System, Boston, MA, 02132, USA.
¹² The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, 90502, USA.
¹³ Center for Genomic Medicine and Department of Anesthesia, Pain, and Critical Care Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA.
¹⁴ Department of Population and Quantitative Health Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA.
¹⁵ Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.
¹⁶ Department of Data Science, University of Mississippi Medical Center, Jackson, MS, 29216, USA.
¹⁷ Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
¹⁸ Division of Pulmonary, Critical Care and Sleep Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
¹⁹ California Pacific Medical Center Research Institute, San Francisco, CA, 94107, USA.
²⁰ Department of Pulmonary Physiology and Sleep Medicine, Sir Charles Gairdner Hospital, Perth, Western Australia, 6009, Australia.
²¹ Sleep Health Service, Respiratory and Sleep Services, Southern Adelaide Local Health Network, Adelaide, South Australia, Australia.
²² Adelaide Institute for Sleep Health, Flinders University, Adelaide, South Australia, Australia.
²³ School of Public Health, University of Adelaide, Adelaide, South Australia, 5000, Australia.
²⁴ Department of Biostatistics and Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI, 48109, USA.
²⁵ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA.
²⁶ Department of Medicine, University of Mississippi Medical Center, Jackson, MS, 39216, USA.
²⁷ Jackson Heart Study, Jackson, MS, 39216, USA.
²⁸ Department of Biostatistics, Boston University School of Public Health, Boston, MA, 02118, USA.
²⁹ Framingham Heart Study, Framingham, MA, 01702, USA.
³⁰ Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York, 10461, USA.
³¹ Department of Genome Sciences, University of Washington, Seattle, WA, 98195, USA.
³² Northwest Genomics Center, Seattle, WA, 98105, USA.
³³ Department of Epidemiology and Carolina Center of Genome Sciences, University of North Carolina, Chapel Hill, NC, 27514, USA.
³⁴ Cardiovascular Health Study, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, WA, 98101, USA.
³⁵ Kaiser Permanente Washington Health Research Institute, Seattle, WA, 98101, USA.
³⁶ Center for Public Health Genomics, University of Virginia, Charlottesville, VA, 22908, USA.
³⁷ Department of Pathology, University of Vermont, Colchester, VT, 05405, USA.
³⁸ Sections of Preventive Medicine and Epidemiology and Cardiology, Department of Medicine, Boston University School of Medicine, Boston, MA, 02118, USA.
³⁹ Department of Epidemiology, Boston University School of Public Health, Boston, MA, 02118, USA.
⁴⁰ Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, 39216, USA.
⁴¹ Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA.

Abstract

Background: Sleep-disordered breathing is a common disorder associated with significant morbidity. The genetic architecture of sleep-disordered breathing remains poorly understood. Through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program, we performed the first whole-genome sequence analysis of sleep-disordered breathing.

Methods: The study sample was comprised of 7988 individuals of diverse ancestry. Common-variant and pathway analyses included an additional 13,257 individuals. We examined five complementary traits describing different aspects of sleep-disordered breathing: the apnea-hypopnea index, average oxyhemoglobin desaturation per event, average and minimum oxyhemoglobin saturation across the sleep episode, and the percentage of sleep with oxyhemoglobin saturation < 90%. We adjusted for age, sex, BMI, study, and family structure using MMSKAT and EMMAX mixed linear model approaches. Additional bioinformatics analyses were performed with MetaXcan, GIGSEA, and ReMap.

Results: We identified a multi-ethnic set-based rare-variant association (p = 3.48 × 10^-8) on chromosome X with ARMCX3. Additional rare-variant associations include ARMCX3-AS1, MRPS33, and C16orf90. Novel common-variant loci were identified in the NRG1 and SLC45A2 regions, and previously associated loci in the IL18RAP and ATP2B4 regions were associated with novel phenotypes. Transcription factor binding site enrichment identified associations with genes implicated with respiratory and craniofacial traits. Additional analyses identified significantly associated pathways.

Conclusions: We have identified the first gene-based rare-variant associations with objectively measured sleep-disordered breathing traits. Our results increase the understanding of the genetic architecture of sleep-disordered breathing and highlight associations in genes that modulate lung development, inflammation, respiratory rhythmogenesis, and HIF1A-mediated hypoxic response.

Keywords: GWAS; Genome-wide association study; Sleep apnea; Sleep-disordered breathing; WGS; Whole-genome sequencing.

Publication types

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

MeSH terms

Alleles
Chromatin Immunoprecipitation Sequencing
Female
Gene Expression Regulation
Genetic Association Studies*
Genetic Predisposition to Disease*
Genome-Wide Association Study*
Genotype
Humans
Male
National Heart, Lung, and Blood Institute (U.S.)
Phenotype
Precision Medicine / methods
Forschung
Signal Transduction
Sleep Apnea Syndromes / diagnosis*
Sleep Apnea Syndromes / etiology*
Sleep Apnea Syndromes / metabolism
Vereinigte Staaten
Whole Genome Sequencing*

Abstract

Publication types

MeSH terms

Grants and funding