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 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.
Liang, J; Cade, BE; He, KY; Wang, H; Lee, J; Sofer, T; Williams, S; Li, R; Chen, H; Gottlieb, DJ; Evans, DS; Guo, X; Gharib, SA; Hale, L; Hillman, DR; Lutsey, PL; Mukherjee, S; Ochs-Balcom, HM; Palmer, LJ; Rhodes, J; Purcell, S; Patel, SR; Saxena, R; Stone, KL; Tang, W; Tranah, GJ; Boerwinkle, E; Lin, X; Liu, Y; Psaty, BM; Vasan, RS; Cho, MH; Manichaikul, A; Silverman, EK; Barr, RG; Rich, SS; Rotter, JI; Wilson, JG; NHLBI Trans-Omics for Precision Medicine (TOPMed), ; TOPMed Sleep Working Group, ; Redline, S; Zhu, X
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