Journal article
Whole-genome association analyses of sleep-disordered breathing phenotypes in the NHLBI TOPMed program
Genome medicine, Vol.13(1), pp.136-136
08/26/2021
DOI: 10.1186/s13073-021-00917-8
PMCID: PMC8394596
PMID: 34446064
Abstract
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.
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.
We identified a multi-ethnic set-based rare-variant association (p = 3.48 × 10
) 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.
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.
Details
- Title: Subtitle
- Whole-genome association analyses of sleep-disordered breathing phenotypes in the NHLBI TOPMed program
- Creators
- Brian E Cade - Brigham and Women's HospitalJiwon Lee - Brigham and Women's HospitalTamar Sofer - Harvard UniversityHeming Wang - Brigham and Women's HospitalMan Zhang - University of Maryland, BaltimoreHan Chen - The University of Texas Health Science Center at HoustonSina A Gharib - University of WashingtonDaniel J Gottlieb - Brigham and Women's HospitalXiuqing Guo - The Lundquist InstituteJacqueline M Lane - Brigham and Women's HospitalJingjing Liang - Case Western Reserve UniversityXihong Lin - Harvard UniversityHao Mei - University of Mississippi Medical CenterSanjay R Patel - University of PittsburghShaun M Purcell - Broad InstituteRicha Saxena - Brigham and Women's HospitalNeomi A Shah - Icahn School of Medicine at Mount SinaiDaniel S Evans - California Pacific Medical CenterCraig L Hanis - The University of Texas Health Science Center at HoustonDavid R Hillman - Sir Charles Gairdner HospitalSutapa Mukherjee - Adelaide Institute for Sleep HealthLyle J Palmer - The University of AdelaideKatie L Stone - California Pacific Medical CenterGregory J Tranah - California Pacific Medical CenterGonçalo R Abecasis - University of MichiganEric A Boerwinkle - The University of Texas Health Science Center at HoustonAdolfo Correa - University of Mississippi Medical CenterL Adrienne Cupples - Boston UniversityRobert C Kaplan - Albert Einstein College of MedicineDeborah A Nickerson - University of WashingtonKari E North - University of North Carolina at Chapel HillBruce M Psaty - University of WashingtonJerome I Rotter - The Lundquist InstituteStephen S Rich - University of VirginiaRussell P Tracy - University of VermontRamachandran S Vasan - Boston UniversityJames G Wilson - University of Mississippi Medical CenterXiaofeng Zhu - Case Western Reserve UniversitySusan Redline - Harvard UniversityNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
- Contributors
- Karin F Hoth (Contributor) - University of Iowa, Psychiatry
- Resource Type
- Journal article
- Publication Details
- Genome medicine, Vol.13(1), pp.136-136
- DOI
- 10.1186/s13073-021-00917-8
- PMID
- 34446064
- PMCID
- PMC8394596
- NLM abbreviation
- Genome Med
- ISSN
- 1756-994X
- eISSN
- 1756-994X
- Grant note
- R01 DK073541 / NIDDK NIH HHS U01 HG004402 / NHGRI NIH HHS U01 AG042124 / NIA NIH HHS R01HL105756 / National Heart, Lung, and Blood Institute (US) HHSN268201100037C / NHLBI NIH HHS U01 AG042139 / NIA NIH HHS R01 HL070839 / NHLBI NIH HHS HHSN268201700004I / NHLBI NIH HHS HHSN268201700003I / NHLBI NIH HHS R01 HL070847 / NHLBI NIH HHS U01HG004402 / National Human Genome Research Institute (US) U01 AG042145 / NIA NIH HHS R01HL071051 / National Heart, Lung, and Blood Institute (US) HHSN268201300002I / National Heart, Lung, and Blood Institute (US) HHSN268201800014I / NHLBI NIH HHS HHSN268201500001I / NHLBI NIH HHS HHSN268201300004I / National Heart, Lung, and Blood Institute (US) U24 HG008956 / NHGRI NIH HHS R01 AR051124 / NIAMS NIH HHS N01-HC-95165 / National Heart, Lung, and Blood Institute (US) UL1 TR000128 / NCATS NIH HHS R01 HL092577 / NHLBI NIH HHS R01 AI085014 / NIAID NIH HHS HHSN268201500003I / NHLBI NIH HHS HHSN268201800015I / NHLBI NIH HHS U01 AR066160 / NIAMS NIH HHS HHSN268201500015C / NHLBI NIH HHS R01 HL143221 / NHLBI NIH HHS HHSN26800001 / National Institutes of Health (US) U01 AG042168 / NIA NIH HHS U01 AG042143 / NIA NIH HHS R01 HL070848 / NHLBI NIH HHS U01 DK062413 / NIDDK NIH HHS HHSN268200960009C / National Heart, Lung, and Blood Institute (US) K01 AG059898 / NIA NIH HHS HHSN268201700005I / NHLBI NIH HHS HHSN268201700002I / NHLBI NIH HHS HHSN268201800012I / NHLBI NIH HHS R01 HL070837 / NHLBI NIH HHS R01 HL070842 / NHLBI NIH HHS R01HL120393 / National Heart, Lung, and Blood Institute (US) HHSN268201300005C / NHLBI NIH HHS R01 AG023629 / NIA NIH HHS UM1 HG008898 / NHGRI NIH HHS HHSN268201800001C / NHLBI NIH HHS R35 HL135818 / NHLBI NIH HHS R01 HL153814 / NHLBI NIH HHS U01 AG042140 / NIA NIH HHS HHSN268201200036C / NHLBI NIH HHS HHSN268200800007C / NHLBI NIH HHS RC2 AR058973 / NIAMS NIH HHS R01 HL070841 / NHLBI NIH HHS HHSN268201800013I / NIMHD NIH HHS R01 HL102830 / NHLBI NIH HHS HHSN268201300001I / National Heart, Lung, and Blood Institute (US) HHSN268201300003I / National Heart, Lung, and Blood Institute (US) HHSN268201800010I / NHLBI NIH HHS U01 DK085501 / NIDDK NIH HHS HHSN268200625226C / National Institutes of Health (US) HHSN268201300005I / National Heart, Lung, and Blood Institute (US) HHSN268201700001I / NHLBI NIH HHS R01 HL070838 / NHLBI NIH HHS HHSN268201800011I / NHLBI NIH HHS U01 AG027810 / NIA NIH HHS R01 HL071194 / NHLBI NIH HHS N01-HC-95164 / National Heart, Lung, and Blood Institute (US)
- Language
- English
- Date published
- 08/26/2021
- Academic Unit
- Psychiatry; Iowa Neuroscience Institute
- Record Identifier
- 9984293753602771
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