Associations of variants in the hexokinase 1 and interleukin 18 receptor regions with oxyhemoglobin saturation during sleep

Brian E. Cade, Han Chen, Adrienne M. Stilp, Tin Louie, Sonia Ancoli-Israel, Raanan Arens, Richard Barfield, Jennifer E. Below, Jianwen Cai, Matthew P. Conomos, Daniel S. Evans, Alexis C. Frazier-Wood, Sina A. Gharib, Kevin J. Gleason, Daniel J. Gottlieb, David R. Hillman, W. Craig Johnson, David J. Lederer, Jiwon Lee, Jose S. LoredoHao Mei, Sutapa Mukherjee, Sanjay R. Patel, Wendy S. Post, Shaun M. Purcell, Alberto R. Ramos, Kathryn J. Reid, Ken Rice, Neomi A. Shah, Tamar Sofer, Kent D. Taylor, Timothy A. Thornton, Heming Wang, Kristine Yaffe, Phyllis C. Zee, Craig L. Hanis, Lyle J. Palmer, Jerome I. Rotter, Katie L. Stone, Gregory J. Tranah, James G. Wilson, Shamil R. Sunyaev, Cathy C. Laurie, Xiaofeng Zhu, Richa Saxena, Xihong Lin, Susan Redline

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


Sleep disordered breathing (SDB)-related overnight hypoxemia is associated with cardiometabolic disease and other comorbidities. Understanding the genetic bases for variations in nocturnal hypoxemia may help understand mechanisms influencing oxygenation and SDB-related mortality. We conducted genome-wide association tests across 10 cohorts and 4 populations to identify genetic variants associated with three correlated measures of overnight oxyhemoglobin saturation: average and minimum oxyhemoglobin saturation during sleep and the percent of sleep with oxyhemoglobin saturation under 90%. The discovery sample consisted of 8,326 individuals. Variants with p < 1 × 10−6 were analyzed in a replication group of 14,410 individuals. We identified 3 significantly associated regions, including 2 regions in multi-ethnic analyses (2q12, 10q22). SNPs in the 2q12 region associated with minimum SpO2 (rs78136548 p = 2.70 × 10−10). SNPs at 10q22 were associated with all three traits including average SpO2 (rs72805692 p = 4.58 × 10−8). SNPs in both regions were associated in over 20,000 individuals and are supported by prior associations or functional evidence. Four additional significant regions were detected in secondary sex-stratified and combined discovery and replication analyses, including a region overlapping Reelin, a known marker of respiratory complex neurons.These are the first genome-wide significant findings reported for oxyhemoglobin saturation during sleep, a phenotype of high clinical interest. Our replicated associations with HK1 and IL18R1 suggest that variants in inflammatory pathways, such as the biologically-plausible NLRP3 inflammasome, may contribute to nocturnal hypoxemia.

Original languageEnglish (US)
Article numbere1007739
JournalPLoS genetics
Issue number4
StatePublished - 2019

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research


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