Faculty, Staff and Student Publications

Language

English

Publication Date

8-26-2021

Journal

Genome Medicine

DOI

10.1186/s13073-021-00917-8

PMID

34446064

PMCID

PMC8394596

PubMedCentral® Posted Date

August 2021

PubMedCentral® Full Text Version

Post-print

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 < 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.

RESULTS: We identified a multi-ethnic set-based rare-variant association (p = 3.48 × 10

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.

Keywords

Alleles, 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

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