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

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

Bibliographical note

Funding Information:
This work was supported by grants HL113338, HL046389, and HL135818 (to S.R.) from the National Heart, Lung, and Blood Institute ( NHLBI ) and HG003054 (to X.Z.) from the National Human Genome Research Institute ( NHGRI ). J.L. was supported by T32HL007567 from the NHLBI . Whole-genome sequencing (WGS) for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the NHLBI . Detailed funding information can be found in the Supplemental Data . We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. The contributions of the investigators of the NHLBI TOPMed Consortium are gratefully acknowledged. A full TOPMed authorship list is available in the Supplemental Data .

Funding Information:
This work was supported by grants HL113338, HL046389, and HL135818 (to S.R.) from the National Heart, Lung, and Blood Institute (NHLBI) and HG003054 (to X.Z.) from the National Human Genome Research Institute (NHGRI). J.L. was supported by T32HL007567 from the NHLBI. Whole-genome sequencing (WGS) for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the NHLBI. Detailed funding information can be found in the Supplemental Data. We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. The contributions of the investigators of the NHLBI TOPMed Consortium are gratefully acknowledged. A full TOPMed authorship list is available in the Supplemental Data.

Publisher Copyright:
© 2019 American Society of Human Genetics

Keywords

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

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