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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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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 &lt;\u200990%. 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified a multi-ethnic set-based rare-variant association (\n                      <jats:italic>p<\/jats:italic>\n                      = 3.48 \u00d7 10\n                      <jats:sup>\u22128<\/jats:sup>\n                      ) on chromosome X with\n                      <jats:italic>ARMCX3<\/jats:italic>\n                      . Additional rare-variant associations include\n                      <jats:italic>ARMCX3-AS1<\/jats:italic>\n                      ,\n                      <jats:italic>MRPS33<\/jats:italic>\n                      , and\n                      <jats:italic>C16orf90<\/jats:italic>\n                      . Novel common-variant loci were identified in the\n                      <jats:italic>NRG1<\/jats:italic>\n                      and\n                      <jats:italic>SLC45A2<\/jats:italic>\n                      regions, and previously associated loci in the\n                      <jats:italic>IL18RAP<\/jats:italic>\n                      and\n                      <jats:italic>ATP2B4<\/jats:italic>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:italic>HIF1A<\/jats:italic>\n                      -mediated hypoxic response.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13073-021-00917-8","type":"journal-article","created":{"date-parts":[[2021,8,26]],"date-time":"2021-08-26T19:18:35Z","timestamp":1630005515000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Whole-genome association analyses of sleep-disordered breathing phenotypes in the NHLBI TOPMed program"],"prefix":"10.1186","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1424-0673","authenticated-orcid":false,"given":"Brian 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All patients have given their written informed consent. The ARIC study was approved by the IRBs of the University of North Carolina at Chapel Hill, Univerity of Minnesota, and Johns Hopkins University. Cleveland Family Study was approved by the IRBs of Case Western Reserve University and Mass General Brigham (formerly Partners HealthCare). The CHS study was approved by the IRBs [or ethics review committee] of University Washington, University of Pittsburgh, and University of California, Sacramento. The Framingham Heart Study was approved by the IRB of the Boston University Medical Center. The JHS study was approved by Jackson State University, Tougaloo College, and the University of Mississippi Medical Center IRBs. The HCHS\/SOL study was approved by the IRBs at each field center, and by the Non-Biomedical IRB at the University of North Carolina at Chapel Hill, to the HCHS\/SOL Data Coordinating Center. All IRBs approving the study are Non-Biomedical IRB at the University of North Carolina at Chapel Hill, Chapel Hill, NC; Einstein IRB at the Albert Einstein College of Medicine of Yeshiva University, Bronx, NY; IRB at Office for the Protection of Research Subjects (OPRS), University of Illinois at Chicago, Chicago, IL; Human Subject Research Office, University of Miami, Miami, FL; and Institutional Review Board of San Diego State University, San Diego, CA. The MESA study was approved by the IRBs at The Lundquist Institute (formerly Los Angeles BioMedical Research Institute) at Harbor-UCLA Medical Center, University of Washington, Wake Forest School of Medicine, Northwestern University, University of Minnesota, Columbia University, and Johns Hopkins University. The MrOS study was approved by the IRBs of the San Francisco Coordinating center (UCSF and California Pacific Medical Center), University of Alabama at Birmingham, University of Minnesota, Stanford University, University of Pittsburgh, Oregon Health and Science University, and University of California, San Diego. The Starr County study was approved by the IRB at the University of Texas Health Science Center at Houston. The WASHS study was approved by the Human Research Ethics Committee of Sir Charles Gairdner Hospital, as well as The University of Western Australia, the Confidentiality of Health Information Committee, and the Human Research Ethics Committee of the Western Australian Department of Health. The research was conducted in strict compliance with the Declaration of Helsinki.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors disclose the following industry funding, which they believe is unrelated to this study. SRP has had grant support through his institution from the ResMed Foundation, Bayer Pharmaceuticals, and Philips Respironics. BMP serves on the Steering Committee of the Yale Open Data Access Project, funded by Johnson & Johnson. KLS has grant funding from Merck. The remaining authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"136"}}