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 Aug 26
ISSN1756-994X
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
HHSN268201800012I / / National Institutes of Health (US) /
HHSN268201200036C / HL / NHLBI NIH HHS / United States
UM1 HG008898 / HG / NHGRI NIH HHS / United States
HHSN268201300004I / / National Heart, Lung, and Blood Institute (US) /
U01 DK085501 / DK / NIDDK NIH HHS / United States
UL1-TR-001079 / / 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
R01HL085251 / / National Heart, Lung, and Blood Institute (US) /
N01-HC-95167 / / National Heart, Lung, and Blood Institute (US) /
3R01HL098433-05S1 / / National Heart, Lung, and Blood Institute (US) /
3R01HL-120393-02S1 / / National Heart, Lung, and Blood Institute (US) /
HHSN268201500001I / HL / NHLBI NIH HHS / United States
N01HC85081 / HL / NHLBI NIH HHS / United States
R35-HL135818 / HL / NHLBI NIH HHS / United States
N01HC85083 / HL / NHLBI NIH HHS / United States
N01-HC-95160 / / National Heart, Lung, and Blood Institute (US) /
R01 HL092577 / HL / NHLBI NIH HHS / United States
R01HL120393 / / National Heart, Lung, and Blood Institute (US) /
HHSN268201300005C / HL / NHLBI NIH HHS / United States
N01-HC-95163 / / National Heart, Lung, and Blood Institute (US) /
R01 HL071194 / HL / NHLBI NIH HHS / United States
KL2-RR024990 / / National Heart, Lung, and Blood Institute (US) /
UL1TR001881 / / National Institutes of Health (US) /
U01 AG042124 / AG / NIA NIH HHS / United States
N01-HC-95166 / / National Heart, Lung, and Blood Institute (US) /
HHSN268201800015I / HB / NHLBI NIH HHS / United States
N01-HC65233 / / National Heart, Lung, and Blood Institute (US) /
R01 HL070837 / HL / NHLBI NIH HHS / United States
N01-HC-95169 / / National Heart, Lung, and Blood Institute (US) /
U24 HG008956 / HG / NHGRI NIH HHS / United States
U01 AG042145 / AG / NIA NIH HHS / United States
R01 HL070848 / HL / NHLBI NIH HHS / United States
N01HC55222 / HL / NHLBI NIH HHS / United States
N01-HC65236 / / National Heart, Lung, and Blood Institute (US) /
R01 HL070839 / HL / NHLBI NIH HHS / United States
N01HC85082 / HL / NHLBI NIH HHS / United States
HHSN268201800010I / / National Institutes of Health (US) /
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
N01-HC-95168 / / National Heart, Lung, and Blood Institute (US) /
R01-HL113338 / / National Heart, Lung, and Blood Institute (US) /
N01-HC-25195 / / National Institutes of Health (US) /
HHSN268201700005I / HL / NHLBI NIH HHS / United States
HHSN26800001 / / National Institutes of Health (US) /
K01-HL135405 / HL / NHLBI NIH HHS / United States
UL1-TR-001420 / / National Heart, Lung, and Blood Institute (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
R01HL071259 / / National Heart, Lung, and Blood Institute (US) /
R01HL103612 / / National Heart, Lung, and Blood Institute (US) /
R35 HL135818 / HL / NHLBI NIH HHS / United States
HHSN268201300005I / / National Heart, Lung, and Blood Institute (US) /
HHSN268201300002I / / National Heart, Lung, and Blood Institute (US) /
3U54HG003273-12S2 / / National Heart, Lung, and Blood Institute (US) /
R01HL086694 / / National Heart, Lung, and Blood Institute (US) /
UL1RR033176 / / National Institutes of Health (US) /
HHSN268201700003I / HL / NHLBI NIH HHS / United States
HHSN268200800007C / HL / NHLBI NIH HHS / United States
R01AG023629 / / National Institute on Aging (US) /
UL1-TR-000040 / / National Heart, Lung, and Blood Institute (US) /
HHSN268200625226C / / National Institutes of Health (US) /
3R01HL-117626-02S1 / / National Heart, Lung, and Blood Institute (US) /
UL1RR025005 / / National Institutes of Health (US) /
R01HL071251 / / National Heart, Lung, and Blood Institute (US) /
R01HL059367 / / National Heart, Lung, and Blood Institute (US) /
HHSN268201800014I / / National Institutes of Health (US) /
HHSN268201700001I / HL / NHLBI NIH HHS / United States
N01-HC65237 / / National Heart, Lung, and Blood Institute (US) /
U01HG004402 / / National Human Genome Research Institute (US) /
RC2 AR058973 / AR / NIAMS NIH HHS / United States
N01-HC-95159 / / National Heart, Lung, and Blood Institute (US) /
R01HL071258 / / National Heart, Lung, and Blood Institute (US) /
U01 AR066160 / AR / NIAMS NIH HHS / United States
U01HL130114 / / National Heart, Lung, and Blood Institute (US) /
N01-HC-95161 / / National Heart, Lung, and Blood Institute (US) /
R01 AI085014 / AI / NIAID NIH HHS / United States
R01HL087652 / / National Heart, Lung, and Blood Institute (US) /
R01HL087641 / / National Heart, Lung, and Blood Institute (US) /
HHSN268201800011I / / National Institutes of Health (US) /
R01 HL070847 / HL / NHLBI NIH HHS / United States
R01HL071205 / / National Heart, Lung, and Blood Institute (US) /
R01HL105756 / / National Heart, Lung, and Blood Institute (US) /
R01 DK073541 / DK / NIDDK NIH HHS / United States
U01 AG042139 / AG / NIA NIH HHS / United States
3R01HL092577-06S1 / / National Heart, Lung, and Blood Institute (US) /
DK063491 / / National Institute of Diabetes and Digestive and Kidney Disease (US) /
N01-HC-95162 / / National Heart, Lung, and Blood Institute (US) /
HHSN268201700002I / HL / NHLBI NIH HHS / United States
R01 HL070842 / HL / NHLBI NIH HHS / United States
HHSN268201300001I / / National Heart, Lung, and Blood Institute (US) /
U01 AG027810 / AG / NIA NIH HHS / United States
N01-HC65234 / / National Heart, Lung, and Blood Institute (US) /
N01HC85080 / HL / NHLBI NIH HHS / United States
R01 AG023629 / AG / NIA NIH HHS / United States
R01 HL153814 / HL / NHLBI NIH HHS / United States
N01-HC65235 / / National Heart, Lung, and Blood Institute (US) /
U01 AG042143 / AG / NIA NIH HHS / United States
HHSN268201800001C / HL / NHLBI NIH HHS / United States
U01HL080295 / / National Heart, Lung, and Blood Institute (US) /
HHSN268201800013I / MD / NIMHD NIH HHS / United States
R01HL071250 / / National Heart, Lung, and Blood Institute (US) /
U54GM115428 / / National Institutes of Health (US) /
HHSN268201300003I / / National Heart, Lung, and Blood Institute (US) /
R01-HL046380 / / National Heart, Lung, and Blood Institute (US) /
3U54HG003067-13S1 / / National Heart, Lung, and Blood Institute (US) /
N01HC85086 / HL / NHLBI NIH HHS / United States
N01HC85079 / HL / NHLBI NIH HHS / United States
HHSN268201100037C / HL / NHLBI NIH HHS / United States