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

TitleSequencing Analysis at 8p23 Identifies Multiple Rare Variants in DLC1 Associated with Sleep-Related Oxyhemoglobin Saturation Level.
Publication TypeJournal Article
Year of Publication2019
AuthorsLiang, 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, R Barr, G, Rich, SS, Rotter, JI, Wilson, JG, Redline, S, Zhu, X
Corporate AuthorsNHLBI Trans-Omics for Precision Medicine (TOPMed), TOPMed Sleep Working Group
JournalAm J Hum Genet
Date Published2019 Nov 07
KeywordsChromosomes, Human, Pair 8, Genetic Linkage, Genome-Wide Association Study, GTPase-Activating Proteins, Humans, Oxyhemoglobins, Sleep, Tumor Suppressor Proteins, Whole Genome Sequencing

Average arterial oxyhemoglobin saturation during sleep (AvSpOS) 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, we observed that six coding and 51 noncoding variants in a gene that encodes the GTPase-activating protein (DLC1) are significantly associated with AvSpOS 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). A risk score for these variants, built on an independent dataset, explains 0.97% of the AvSpOS 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 AvSpOS. Multiple sources of information, including genetic variants, gene expression, and methylation, consistently suggest that DLC1 is a gene associated with AvSpOS.

Alternate JournalAm J Hum Genet
PubMed ID31668705
PubMed Central IDPMC6849112
Grant ListR01 HG003054 / HG / NHGRI NIH HHS / United States
R01 HL046380 / HL / NHLBI NIH HHS / United States
U01 HL130114 / HL / NHLBI NIH HHS / United States
R01 HL113338 / HL / NHLBI NIH HHS / United States
T32 HL007567 / HL / NHLBI NIH HHS / United States
K01 HL135405 / HL / NHLBI NIH HHS / United States
R35 HL135818 / HL / NHLBI NIH HHS / United States
R01 HG011052 / HG / NHGRI NIH HHS / United States

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