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

Medientyp: E-Artikel
Titel: Whole-genome association analyses of sleep-disordered breathing phenotypes in the NHLBI TOPMed program
Beteiligte: 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.; [...]
Erschienen: Springer Science and Business Media LLC, 2021
Erschienen in: Genome Medicine
Sprache: Englisch
DOI: 10.1186/s13073-021-00917-8
ISSN: 1756-994X
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Beschreibung: <jats:title>Abstract</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>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.</jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>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.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>We identified a multi-ethnic set-based rare-variant association (<jats:italic>p</jats:italic> = 3.48 × 10<jats:sup>−8</jats:sup>) on chromosome X with <jats:italic>ARMCX3</jats:italic>. Additional rare-variant associations include <jats:italic>ARMCX3-AS1</jats:italic>, <jats:italic>MRPS33</jats:italic>, and <jats:italic>C16orf90</jats:italic>. Novel common-variant loci were identified in the <jats:italic>NRG1</jats:italic> and <jats:italic>SLC45A2</jats:italic> regions, and previously associated loci in the <jats:italic>IL18RAP</jats:italic> and <jats:italic>ATP2B4</jats:italic> 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.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusions</jats:title> <jats:p>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 <jats:italic>HIF1A</jats:italic>-mediated hypoxic response.</jats:p> </jats:sec>
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