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

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 Nation...

Full description

Saved in:
Bibliographic Details
Published in:American journal of human genetics 2019-11, Vol.105 (5), p.1057-1068
Main Authors: Liang, Jingjing, Cade, Brian E., He, Karen Y., Wang, Heming, Lee, Jiwon, Sofer, Tamar, Williams, Stephanie, Li, Ruitong, Chen, Han, Gottlieb, Daniel J., Evans, Daniel S., Guo, Xiuqing, Gharib, Sina A., Hale, Lauren, Hillman, David R., Lutsey, Pamela L., Mukherjee, Sutapa, Ochs-Balcom, Heather M., Palmer, Lyle J., Rhodes, Jessica, Purcell, Shaun, Patel, Sanjay R., Saxena, Richa, Stone, Katie L., Tang, Weihong, Tranah, Gregory J., Boerwinkle, Eric, Lin, Xihong, Liu, Yongmei, Psaty, Bruce M., Vasan, Ramachandran S., Cho, Michael H., Manichaikul, Ani, Silverman, Edwin K., Barr, R. Graham, Rich, Stephen S., Rotter, Jerome I., Wilson, James G., Redline, Susan, Zhu, Xiaofeng
Format: Article
Language:English
Subjects:
arterial oxyhemoglobin saturation
Chromosomes, Human, Pair 8 - genetics
Genetic Linkage - genetics
Genome-Wide Association Study
GTPase-Activating Proteins - genetics
Humans
linkage analysis
Oxyhemoglobins - genetics
Sleep - genetics
sleep-disordered breathing
The Trans-Omics for Precision Medicine (TOPMed) program
Tumor Suppressor Proteins - genetics
Whole Genome Sequencing - methods
whole-genome sequencing association analyses
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0002-9297
1537-6605
1537-6605
DOI:10.1016/j.ajhg.2019.10.002