Sequencing Analysis at 8p23 Identifies Multiple Rare Variants in DLC1 Associated with Sleep-Related Oxyhemoglobin Saturation Level

Am J Hum Genet. 2019 Nov 7;105(5):1057-1068. doi: 10.1016/j.ajhg.2019.10.002. Epub 2019 Oct 24.


Average arterial oxyhemoglobin saturation during sleep (AvSpO2S) is a clinically relevant measure of physiological stress associated with sleep-disordered breathing, and this measure predicts incident cardiovascular disease and mortality. Using high-depth whole-genome sequencing data from the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) project and focusing on genes with linkage evidence on chromosome 8p23,1,2 we observed that six coding and 51 noncoding variants in a gene that encodes the GTPase-activating protein (DLC1) are significantly associated with AvSpO2S and replicated in independent subjects. The combined DLC1 association evidence of discovery and replication cohorts reaches genome-wide significance in European Americans (p = 7.9 × 10-7). A risk score for these variants, built on an independent dataset, explains 0.97% of the AvSpO2S variation and contributes to the linkage evidence. The 51 noncoding variants are enriched in regulatory features in a human lung fibroblast cell line and contribute to DLC1 expression variation. Mendelian randomization analysis using these variants indicates a significant causal effect of DLC1 expression in fibroblasts on AvSpO2S. Multiple sources of information, including genetic variants, gene expression, and methylation, consistently suggest that DLC1 is a gene associated with AvSpO2S.

Keywords: The Trans-Omics for Precision Medicine (TOPMed) program; arterial oxyhemoglobin saturation; linkage analysis; sleep-disordered breathing; whole-genome sequencing association analyses.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Chromosomes, Human, Pair 8 / genetics*
  • GTPase-Activating Proteins / genetics*
  • Genetic Linkage / genetics
  • Genome-Wide Association Study
  • Humans
  • Oxyhemoglobins / genetics*
  • Sleep / genetics*
  • Tumor Suppressor Proteins / genetics*
  • Whole Genome Sequencing / methods


  • DLC1 protein, human
  • GTPase-Activating Proteins
  • Oxyhemoglobins
  • Tumor Suppressor Proteins