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

TitleWhole-genome association analyses of sleep-disordered breathing phenotypes in the NHLBI TOPMed program.
Publication TypeJournal Article
Year of Publication2021
AuthorsCade, BE, Lee, J, Sofer, T, Wang, H, Zhang, M, Chen, H, Gharib, SA, Gottlieb, DJ, Guo, X, Lane, JM, Liang, J, Lin, X, Mei, H, Patel, SR, Purcell, SM, Saxena, R, Shah, NA, Evans, DS, Hanis, CL, Hillman, DR, Mukherjee, S, Palmer, LJ, Stone, KL, Tranah, GJ, Abecasis, GR, Boerwinkle, E, Correa, A, L Cupples, A, Kaplan, RC, Nickerson, DA, North, KE, Psaty, BM, Rotter, JI, Rich, SS, Tracy, RP, Vasan, RS, Wilson, JG, Zhu, X, Redline, S
Corporate AuthorsNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Sleep Working Group
JournalGenome Med
Volume13
Issue1
Pagination136
Date Published2021 08 26
ISSN1756-994X
KeywordsAlleles, 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, Research, Signal Transduction, Sleep Apnea Syndromes, United States, Whole Genome Sequencing
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

RESULTS: 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.

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.

DOI10.1186/s13073-021-00917-8
Alternate JournalGenome Med
PubMed ID34446064
PubMed Central IDPMC8394596
Grant ListR01 HL070841 / HL / NHLBI NIH HHS / United States
R01 HL070837 / HL / NHLBI NIH HHS / United States
R01 HL070839 / HL / NHLBI NIH HHS / United States
R35 HL135818 / HL / NHLBI NIH HHS / United States
HHSN268201700003I / HL / NHLBI NIH HHS / United States
R01 HL143221 / HL / NHLBI NIH HHS / United States
R01HL105756 / / National Heart, Lung, and Blood Institute (US) /
HHSN268201300003I / / National Heart, Lung, and Blood Institute (US) /
U01 DK085501 / DK / NIDDK NIH HHS / United States
UM1 HG008898 / HG / NHGRI NIH HHS / United States
HHSN268201300004I / / National Heart, Lung, and Blood Institute (US) /
R01 HL070838 / HL / NHLBI NIH HHS / United States
U01 AG042140 / AG / NIA NIH HHS / United States
UL1 TR000128 / TR / NCATS NIH HHS / United States
U01 AG042168 / AG / NIA NIH HHS / United States
HHSN268201500001I / HL / NHLBI NIH HHS / United States
U01 DK062413 / DK / NIDDK NIH HHS / United States
K01 AG059898 / AG / NIA NIH HHS / United States
R01 HL092577 / HL / NHLBI NIH HHS / United States
R01HL120393 / / National Heart, Lung, and Blood Institute (US) /
HHSN268201300005C / HL / NHLBI NIH HHS / United States
R01 HL071194 / HL / NHLBI NIH HHS / United States
U01 AG042124 / AG / NIA NIH HHS / United States
HHSN268201800015I / HB / NHLBI NIH HHS / United States
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HHSN268201800012I / HB / NHLBI NIH HHS / United States
R01 HL070848 / HL / NHLBI NIH HHS / United States
U01 AG042145 / AG / NIA NIH HHS / United States
HHSN268200960009C / / National Heart, Lung, and Blood Institute (US) /
HHSN268201500015C / HL / NHLBI NIH HHS / United States
R01HL071051 / / National Heart, Lung, and Blood Institute (US) /
U01 HG004402 / HG / NHGRI NIH HHS / United States
HHSN268201700005I / HL / NHLBI NIH HHS / United States
HHSN26800001 / / National Institutes of Health (US) /
HHSN268201500003I / HL / NHLBI NIH HHS / United States
HHSN268201700004I / HL / NHLBI NIH HHS / United States
N01-HC-95165 / / National Heart, Lung, and Blood Institute (US) /
R01 HL102830 / HL / NHLBI NIH HHS / United States
N01-HC-95164 / / National Heart, Lung, and Blood Institute (US) /
R01 AR051124 / AR / NIAMS NIH HHS / United States
HHSN268201300005I / / National Heart, Lung, and Blood Institute (US) /
HHSN268201300002I / / National Heart, Lung, and Blood Institute (US) /
HHSN268201200036C / HL / NHLBI NIH HHS / United States
HHSN268201800011I / HB / NHLBI NIH HHS / United States
HHSN268201800010I / HB / NHLBI NIH HHS / United States
HHSN268200800007C / HL / NHLBI NIH HHS / United States
HHSN268200625226C / / National Institutes of Health (US) /
HHSN268201700001I / HL / NHLBI NIH HHS / United States
U01HG004402 / / National Human Genome Research Institute (US) /
RC2 AR058973 / AR / NIAMS NIH HHS / United States
U01 AR066160 / AR / NIAMS NIH HHS / United States
R01 AI085014 / AI / NIAID NIH HHS / United States
R01 HL070847 / HL / NHLBI NIH HHS / United States
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HHSN268201700002I / HL / NHLBI NIH HHS / United States
R01 HL070842 / HL / NHLBI NIH HHS / United States
HHSN268201300001I / / National Heart, Lung, and Blood Institute (US) /
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R01 AG023629 / AG / NIA NIH HHS / United States
R01 HL153814 / HL / NHLBI NIH HHS / United States
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HHSN268201800013I / MD / NIMHD NIH HHS / United States
K01 HL135405 / HL / NHLBI NIH HHS / United States
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HHSN268201100037C / HL / NHLBI NIH HHS / United States