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

NHLBI Trans-Omics for Precision Medicine (TOPMed)

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1057-1068
Number of pages12
JournalAmerican Journal of Human Genetics
Volume105
Issue number5
DOIs
StatePublished - Nov 7 2019
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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