You are here
Whole-genome association analyses of sleep-disordered breathing phenotypes in the NHLBI TOPMed program.
Wednesday,2021-12-15 18:06 America/Los_Angeles — ecterry
| Title | Whole-genome association analyses of sleep-disordered breathing phenotypes in the NHLBI TOPMed program. |
| Publication Type | Journal Article |
| Year of Publication | 2021 |
| Authors | Cade, 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, EA, Correa, A, Cupples, AL, Kaplan, RC, Nickerson, DA, North, KE, Psaty, BM, Rotter, JI, Rich, SS, Tracy, RP, Vasan, RS, Wilson, JG, Zhu, X, Redline, S |
| Corporate/Institutional Authors | NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Sleep Working Group |
| Journal | Genome Med |
| Volume | 13 |
| Issue | 1 |
| Pagination | 136 |
| Date Published | 2021 08 26 |
| ISSN | 1756-994X |
| Abstract | <p><b>BACKGROUND: </b>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.</p><p><b>METHODS: </b>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.</p><p><b>RESULTS: </b>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.</p><p><b>CONCLUSIONS: </b>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.</p> |
| DOI | 10.1186/s13073-021-00917-8 |
| Alternate Journal | Genome Med |
| PubMed ID | 34446064 |
| PubMed Central ID | PMC8394596 |
| Grant List | R01 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 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 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 R01 HL070837 / HL / NHLBI NIH HHS / United States U24 HG008956 / HG / NHGRI NIH HHS / United States U01 AG042145 / AG / NIA NIH HHS / United States R01 HL070848 / HL / NHLBI NIH HHS / United States R01 HL070839 / 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 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 R35 HL135818 / HL / NHLBI NIH HHS / United States HHSN268201300005I / / National Heart, Lung, and Blood Institute (US) / HHSN268201300002I / / National Heart, Lung, and Blood Institute (US) / HHSN268201700003I / HL / NHLBI NIH HHS / United States HHSN268200800007C / HL / NHLBI NIH HHS / United States HHSN268200625226C / / National Institutes of Health (US) / HHSN268201800014I / / 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 HHSN268201800011I / / National Institutes of Health (US) / R01 HL070847 / HL / NHLBI NIH HHS / United States R01HL105756 / / National Heart, Lung, and Blood Institute (US) / R01 DK073541 / DK / NIDDK NIH HHS / United States U01 AG042139 / AG / NIA NIH HHS / United States 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 R01 AG023629 / AG / NIA NIH HHS / United States R01 HL153814 / HL / NHLBI NIH HHS / United States U01 AG042143 / AG / NIA NIH HHS / United States HHSN268201800001C / HL / NHLBI NIH HHS / United States HHSN268201800013I / MD / NIMHD NIH HHS / United States HHSN268201300003I / / National Heart, Lung, and Blood Institute (US) / HHSN268201100037C / HL / NHLBI NIH HHS / United States |
ePub date:
21/08