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

NHLBI Trans-Omics for Precision Medicine (TOPMed), Jingjing Liang, Brian E. Cade, Karen Y. He, Heming Wang, Jiwon Lee, Tamar Sofer, Stephanie Williams, Ruitong Li, Han Chen, Daniel J. Gottlieb, Daniel S. Evans, Xiuqing Guo, Sina A. Gharib, Lauren Hale, David R. Hillman, Pamela L. Lutsey, Sutapa Mukherjee, Heather M. Ochs-Balcom, Lyle J. PalmerJessica Rhodes, Shaun Purcell, Sanjay R. Patel, Richa Saxena, Katie L. Stone, Weihong Tang, Gregory J. Tranah, Eric Boerwinkle, Xihong Lin, Yongmei Liu, Bruce M. Psaty, Ramachandran S. Vasan, Michael H. Cho, Ani Manichaikul, Edwin K. Silverman, R. Graham Barr, Stephen S. Rich, Jerome I. Rotter, James G. Wilson, Susan Redline, Xiaofeng Zhu

    Research output: Contribution to journalArticlepeer-review

    7 Citations (Scopus)


    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
    Pages (from-to)1057-1068
    Number of pages12
    JournalAmerican Journal of Human Genetics
    Issue number5
    Publication statusPublished - 7 Nov 2019


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


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