Genome Medicine (Aug 2021)
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
Affiliations
- Brian E. Cade
- Division of Sleep and Circadian Disorders, Brigham and Women’s Hospital, Harvard Medical School
- Jiwon Lee
- Division of Sleep and Circadian Disorders, Brigham and Women’s Hospital, Harvard Medical School
- Tamar Sofer
- Division of Sleep and Circadian Disorders, Brigham and Women’s Hospital, Harvard Medical School
- Heming Wang
- Division of Sleep and Circadian Disorders, Brigham and Women’s Hospital, Harvard Medical School
- Man Zhang
- Department of Medicine, University of Maryland School of Medicine
- Han Chen
- Human Genetics Center, Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston
- Sina A. Gharib
- Computational Medicine Core, Center for Lung Biology, UW Medicine Sleep Center, Division of Pulmonary, Critical Care and Sleep Medicine, University of Washington
- Daniel J. Gottlieb
- Division of Sleep and Circadian Disorders, Brigham and Women’s Hospital, Harvard Medical School
- Xiuqing Guo
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
- Jacqueline M. Lane
- Division of Sleep and Circadian Disorders, Brigham and Women’s Hospital, Harvard Medical School
- Jingjing Liang
- Department of Population and Quantitative Health Sciences, School of Medicine, Case Western Reserve University
- Xihong Lin
- Department of Biostatistics, Harvard T.H. Chan School of Public Health
- Hao Mei
- Department of Data Science, University of Mississippi Medical Center
- Sanjay R. Patel
- Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh
- Shaun M. Purcell
- Division of Sleep and Circadian Disorders, Brigham and Women’s Hospital, Harvard Medical School
- Richa Saxena
- Division of Sleep and Circadian Disorders, Brigham and Women’s Hospital, Harvard Medical School
- Neomi A. Shah
- Division of Pulmonary, Critical Care and Sleep Medicine, Icahn School of Medicine at Mount Sinai
- Daniel S. Evans
- California Pacific Medical Center Research Institute
- Craig L. Hanis
- Human Genetics Center, Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston
- David R. Hillman
- Department of Pulmonary Physiology and Sleep Medicine, Sir Charles Gairdner Hospital
- Sutapa Mukherjee
- Sleep Health Service, Respiratory and Sleep Services, Southern Adelaide Local Health Network
- Lyle J. Palmer
- School of Public Health, University of Adelaide
- Katie L. Stone
- California Pacific Medical Center Research Institute
- Gregory J. Tranah
- California Pacific Medical Center Research Institute
- NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
- Gonçalo R. Abecasis
- Department of Biostatistics and Center for Statistical Genetics, University of Michigan School of Public Health
- Eric A. Boerwinkle
- Human Genetics Center, Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston
- Adolfo Correa
- Department of Medicine, University of Mississippi Medical Center
- L. Adrienne Cupples
- Department of Biostatistics, Boston University School of Public Health
- Robert C. Kaplan
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine
- Deborah A. Nickerson
- Department of Genome Sciences, University of Washington
- Kari E. North
- Department of Epidemiology and Carolina Center of Genome Sciences, University of North Carolina
- Bruce M. Psaty
- Cardiovascular Health Study, Departments of Medicine, Epidemiology, and Health Services, University of Washington
- Jerome I. Rotter
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
- Stephen S. Rich
- Center for Public Health Genomics, University of Virginia
- Russell P. Tracy
- Department of Pathology, University of Vermont
- Ramachandran S. Vasan
- Framingham Heart Study
- James G. Wilson
- Department of Physiology and Biophysics, University of Mississippi Medical Center
- Xiaofeng Zhu
- Department of Population and Quantitative Health Sciences, School of Medicine, Case Western Reserve University
- Susan Redline
- Division of Sleep and Circadian Disorders, Brigham and Women’s Hospital, Harvard Medical School
- TOPMed Sleep Working Group
- DOI
- https://doi.org/10.1186/s13073-021-00917-8
- Journal volume & issue
-
Vol. 13,
no. 1
pp. 1 – 17
Abstract
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
- Sleep-disordered breathing
- Sleep apnea
- Whole-genome sequencing
- WGS
- Genome-wide association study
- GWAS
