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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. Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Citation

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 Palmer, Jessica 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, NHLBI Trans-Omics for Precision Medicine (TOPMed), TOPMed Sleep Working Group, Susan Redline, Xiaofeng Zhu. Sequencing Analysis at 8p23 Identifies Multiple Rare Variants in DLC1 Associated with Sleep-Related Oxyhemoglobin Saturation Level. American journal of human genetics. 2019 Nov 07;105(5):1057-1068

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PMID: 31668705

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