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Whole-genome association analyses of sleep-disordered breathing phenotypes in the NHLBI TOPMed program
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 ana...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394596/ https://www.ncbi.nlm.nih.gov/pubmed/34446064 http://dx.doi.org/10.1186/s13073-021-00917-8 |
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author | Cade, Brian E. Lee, Jiwon Sofer, Tamar Wang, Heming Zhang, Man Chen, Han Gharib, Sina A. Gottlieb, Daniel J. Guo, Xiuqing Lane, Jacqueline M. Liang, Jingjing Lin, Xihong Mei, Hao Patel, Sanjay R. Purcell, Shaun M. Saxena, Richa Shah, Neomi A. Evans, Daniel S. Hanis, Craig L. Hillman, David R. Mukherjee, Sutapa Palmer, Lyle J. Stone, Katie L. Tranah, Gregory J. Abecasis, Gonçalo R. Boerwinkle, Eric A. Correa, Adolfo Cupples, L. Adrienne Kaplan, Robert C. Nickerson, Deborah A. North, Kari E. Psaty, Bruce M. Rotter, Jerome I. Rich, Stephen S. Tracy, Russell P. Vasan, Ramachandran S. Wilson, James G. Zhu, Xiaofeng Redline, Susan |
author_facet | Cade, Brian E. Lee, Jiwon Sofer, Tamar Wang, Heming Zhang, Man Chen, Han Gharib, Sina A. Gottlieb, Daniel J. Guo, Xiuqing Lane, Jacqueline M. Liang, Jingjing Lin, Xihong Mei, Hao Patel, Sanjay R. Purcell, Shaun M. Saxena, Richa Shah, Neomi A. Evans, Daniel S. Hanis, Craig L. Hillman, David R. Mukherjee, Sutapa Palmer, Lyle J. Stone, Katie L. Tranah, Gregory J. Abecasis, Gonçalo R. Boerwinkle, Eric A. Correa, Adolfo Cupples, L. Adrienne Kaplan, Robert C. Nickerson, Deborah A. North, Kari E. Psaty, Bruce M. Rotter, Jerome I. Rich, Stephen S. Tracy, Russell P. Vasan, Ramachandran S. Wilson, James G. Zhu, Xiaofeng Redline, Susan |
author_sort | Cade, Brian E. |
collection | PubMed |
description | 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13073-021-00917-8. |
format | Online Article Text |
id | pubmed-8394596 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-83945962021-08-30 Whole-genome association analyses of sleep-disordered breathing phenotypes in the NHLBI TOPMed program Cade, Brian E. Lee, Jiwon Sofer, Tamar Wang, Heming Zhang, Man Chen, Han Gharib, Sina A. Gottlieb, Daniel J. Guo, Xiuqing Lane, Jacqueline M. Liang, Jingjing Lin, Xihong Mei, Hao Patel, Sanjay R. Purcell, Shaun M. Saxena, Richa Shah, Neomi A. Evans, Daniel S. Hanis, Craig L. Hillman, David R. Mukherjee, Sutapa Palmer, Lyle J. Stone, Katie L. Tranah, Gregory J. Abecasis, Gonçalo R. Boerwinkle, Eric A. Correa, Adolfo Cupples, L. Adrienne Kaplan, Robert C. Nickerson, Deborah A. North, Kari E. Psaty, Bruce M. Rotter, Jerome I. Rich, Stephen S. Tracy, Russell P. Vasan, Ramachandran S. Wilson, James G. Zhu, Xiaofeng Redline, Susan Genome Med Research 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13073-021-00917-8. BioMed Central 2021-08-26 /pmc/articles/PMC8394596/ /pubmed/34446064 http://dx.doi.org/10.1186/s13073-021-00917-8 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Cade, Brian E. Lee, Jiwon Sofer, Tamar Wang, Heming Zhang, Man Chen, Han Gharib, Sina A. Gottlieb, Daniel J. Guo, Xiuqing Lane, Jacqueline M. Liang, Jingjing Lin, Xihong Mei, Hao Patel, Sanjay R. Purcell, Shaun M. Saxena, Richa Shah, Neomi A. Evans, Daniel S. Hanis, Craig L. Hillman, David R. Mukherjee, Sutapa Palmer, Lyle J. Stone, Katie L. Tranah, Gregory J. Abecasis, Gonçalo R. Boerwinkle, Eric A. Correa, Adolfo Cupples, L. Adrienne Kaplan, Robert C. Nickerson, Deborah A. North, Kari E. Psaty, Bruce M. Rotter, Jerome I. Rich, Stephen S. Tracy, Russell P. Vasan, Ramachandran S. Wilson, James G. Zhu, Xiaofeng Redline, Susan Whole-genome association analyses of sleep-disordered breathing phenotypes in the NHLBI TOPMed program |
title | Whole-genome association analyses of sleep-disordered breathing phenotypes in the NHLBI TOPMed program |
title_full | Whole-genome association analyses of sleep-disordered breathing phenotypes in the NHLBI TOPMed program |
title_fullStr | Whole-genome association analyses of sleep-disordered breathing phenotypes in the NHLBI TOPMed program |
title_full_unstemmed | Whole-genome association analyses of sleep-disordered breathing phenotypes in the NHLBI TOPMed program |
title_short | Whole-genome association analyses of sleep-disordered breathing phenotypes in the NHLBI TOPMed program |
title_sort | whole-genome association analyses of sleep-disordered breathing phenotypes in the nhlbi topmed program |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394596/ https://www.ncbi.nlm.nih.gov/pubmed/34446064 http://dx.doi.org/10.1186/s13073-021-00917-8 |
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