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

Publication ,  Journal Article
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 ...
Published in: Am J Hum Genet
November 7, 2019

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.

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Published In

Am J Hum Genet

DOI

EISSN

1537-6605

Publication Date

November 7, 2019

Volume

105

Issue

5

Start / End Page

1057 / 1068

Location

United States

Related Subject Headings

  • Whole Genome Sequencing
  • Tumor Suppressor Proteins
  • Sleep
  • Oxyhemoglobins
  • Humans
  • Genome-Wide Association Study
  • Genetics & Heredity
  • Genetic Linkage
  • GTPase-Activating Proteins
  • Chromosomes, Human, Pair 8
 

Citation

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Liang, J., Cade, B. E., He, K. Y., Wang, H., Lee, J., Sofer, T., … Zhu, X. (2019). Sequencing Analysis at 8p23 Identifies Multiple Rare Variants in DLC1 Associated with Sleep-Related Oxyhemoglobin Saturation Level. Am J Hum Genet, 105(5), 1057–1068. https://doi.org/10.1016/j.ajhg.2019.10.002
Liang, Jingjing, Brian E. Cade, Karen Y. He, Heming Wang, Jiwon Lee, Tamar Sofer, Stephanie Williams, et al. “Sequencing Analysis at 8p23 Identifies Multiple Rare Variants in DLC1 Associated with Sleep-Related Oxyhemoglobin Saturation Level.Am J Hum Genet 105, no. 5 (November 7, 2019): 1057–68. https://doi.org/10.1016/j.ajhg.2019.10.002.
Liang J, Cade BE, He KY, Wang H, Lee J, Sofer T, et al. Sequencing Analysis at 8p23 Identifies Multiple Rare Variants in DLC1 Associated with Sleep-Related Oxyhemoglobin Saturation Level. Am J Hum Genet. 2019 Nov 7;105(5):1057–68.
Liang, Jingjing, et al. “Sequencing Analysis at 8p23 Identifies Multiple Rare Variants in DLC1 Associated with Sleep-Related Oxyhemoglobin Saturation Level.Am J Hum Genet, vol. 105, no. 5, Nov. 2019, pp. 1057–68. Pubmed, doi:10.1016/j.ajhg.2019.10.002.
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. Sequencing Analysis at 8p23 Identifies Multiple Rare Variants in DLC1 Associated with Sleep-Related Oxyhemoglobin Saturation Level. Am J Hum Genet. 2019 Nov 7;105(5):1057–1068.
Journal cover image

Published In

Am J Hum Genet

DOI

EISSN

1537-6605

Publication Date

November 7, 2019

Volume

105

Issue

5

Start / End Page

1057 / 1068

Location

United States

Related Subject Headings

  • Whole Genome Sequencing
  • Tumor Suppressor Proteins
  • Sleep
  • Oxyhemoglobins
  • Humans
  • Genome-Wide Association Study
  • Genetics & Heredity
  • Genetic Linkage
  • GTPase-Activating Proteins
  • Chromosomes, Human, Pair 8