Researchers identify genetic variations linked to oxygen drops during sleep – National Institutes of Health

News Release

Thursday, October 24, 2019

Researchers have identified 57 genetic variations ofagenestrongly associated withdeclinesinbloodoxygen levelsduring sleep. Low oxygen levels during sleep are a clinical indicator of the severity of sleep apnea, a disorder that increases the risk of heart disease, dementia, and death. The study, published today in theAmerican Journal of Human Genetics, was funded by the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health.

A persons average blood oxygen levels during sleep are hereditary, and relatively easy to measure, said study author Susan Redline, M.D., senior physician in the Division of Sleep and Circadian Disorders at Brigham and Womens Hospital, and professor at Harvard Medical School, Boston. Studying the genetic basis of this trait can help explain why some people are more susceptible to sleep disordered breathing and its related morbidities.

When we sleep, the oxygen level in our blood drops, due to interruptions in breathing. Lung and sleep disorders tend to decrease those levels further, and dangerously so. But the range of those levels during sleep varies widely between individuals and, researchers suspect, is greatly influenced by genetics.

Despite the key roleblood oxygen levelsplayin health outcomes,theinfluenceof genetics on theirvariabilityremains understudied. The current findings contribute toa betterunderstanding, particularly because researcherslookedat overnight measurementsof oxygen levels. Thoseprovide more variability than daytime levelsdue to the stressesassociated withdisordered breathing occurring during sleep.

The researchers analyzed whole genome sequence data from the NHLBIs Trans-Omics for Precision Medicine (TOPMed) program. Tostrengthenthe data,they incorporated results of family-basedlinkage analysis, a method for mapping genes that carry hereditary traits to their location in the genome. Themethod usesdata fromfamilies with several members affected by aparticulardisorder.

This study highlights theadvantage of using family data in searching for rare variants, which is often missed in genome-wide association studies, said James Kiley, Ph.D., director of the Division of Lung Diseases at NHLBI. It showed that, when guided by family linkage data, whole genome sequence analysis can identify rare variants that signal disease risks, even with a small sample. In this case, the initial discovery was done with fewer than 500 samples.

The newly identified 57 variants of the DLC1 gene were clearly associated with the fluctuation in oxygen levels during sleep. In fact, they explained almost 1% ofthevariability in the oxygen levels in European Americans, which is relatively high for complex genetic phenotypes, or traits, that are influenced by myriad variants.

Notably,51 of the 57genetic variantsinfluence and regulate human lung fibroblast cells, a type of cell producing scar tissue in the lungs, according to study author XiaofengZhu, Ph.D., professor at the Case Western Reserve University School of Medicine, Cleveland.

This is important becauseMendelian Randomization analysis, a statistical approach for testing causal relationship between an exposure and an outcome, shows a potential causal relationship between how the DLC1 gene modifies fibroblasts cells andthechanges in oxygen levels during sleep, he said.

Thisrelationship,Kileyadded,suggests thata shared molecular pathway, or a common mechanism,may beinfluencing a persons susceptibility to the lack of oxygen caused by sleep disordered breathingand other lung illnesses such as emphysema.

The project was jointly led by Zhu and Redline, who also directs the National Sleep Research Resource, supported by NHLBI.

About theNational Heart, Lung, and Blood Institute (NHLBI): NHLBI is the global leader in conducting and supporting research in heart, lung, and blood diseases and sleep disorders that advances scientific knowledge, improves public health, and saves lives. For more information, visithttps://www.nhlbi.nih.gov.

About the National Institutes of Health (NIH):NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

NIHTurning Discovery Into Health

Sequencing analysis at 8p23 identifies multiple rare variants in DLC1 associated with sleep related oxyhemoglobin saturation level.

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Researchers identify genetic variations linked to oxygen drops during sleep - National Institutes of Health