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Am J Hum Genet. 2019 Nov 7;105(5):1057-1068. doi: 10.1016/j.ajhg.2019.10.002. Epub 2019 Oct 24.

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

Author information

1
Department of Population and Quantitative Health Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
2
Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA 02115, USA; Division of Sleep Medicine, Harvard Medical School, Boston, MA, 02115, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA.
3
Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA 02115, USA.
4
Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA 02115, USA; Division of Sleep Medicine, Harvard Medical School, Boston, MA, 02115, USA.
5
Human Genetics Center, Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Center for Precision Health, School of Public Health and School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
6
Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA 02115, USA; Division of Sleep Medicine, Harvard Medical School, Boston, MA, 02115, USA; VA Boston Healthcare System, Boston, MA 02132, USA.
7
California Pacific Medical Center Research Institute, San Francisco, CA 94107, USA.
8
Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90509, USA; Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90509, USA.
9
Department of Medicine, Computational Medicine Core, Center for Lung Biology, UW Medicine Sleep Center, University of Washington, Seattle, WA 98195, USA.
10
Family, Population, and Preventive Medicine, Program in Public Health, Stony Brook University School of Medicine, Stony Brook, NY 11794, USA.
11
Department of Pulmonary Physiology and Sleep Medicine, Sir Charles Gairdner Hospital, Perth, Western Australia 6009, Australia.
12
Division of Epidemiology & Community Health, School of Public Health, University of Minnesota, Minneapolis, MN 55455, USA.
13
Sleep Health Service, Respiratory and Sleep Service, Southern Adelaide Local Health Network, Adelaide, South Australia 5042, Australia; Adelaide Institute for Sleep Health, Flinders University, Adelaide, South Australia 5042, Australia.
14
Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, University at Buffalo, Buffalo, NY 14214, USA.
15
School of Public Health, University of Adelaide, South Australia 5000, Australia.
16
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA(19)Center for Genomic Medicine and Department of Anesthesia, Pain and Critical Care Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Anesthesia, Pain and Critical Care Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
17
Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
18
Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA 02115, USA; Division of Sleep Medicine, Harvard Medical School, Boston, MA, 02115, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA(19)Center for Genomic Medicine and Department of Anesthesia, Pain and Critical Care Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Anesthesia, Pain and Critical Care Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
19
Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN 55454, USA.
20
Human Genetics Center, Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
21
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
22
Department of Medicine, Division of Cardiology, Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC 27710, USA.
23
Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services, University of Washington, Seattle, WA 98101, USA; Kaiser Permanente Washington Health Research Institute, Seattle, WA 98101, USA.
24
Framingham Heart Study, Framingham, MA 01702, USA; Section of Preventive Medicine and Epidemiology, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA; Section Cardiology, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA; Department of Epidemiology, Boston University School of Public Health, Boston, MA 02118, USA.
25
Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
26
Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA; Department of Public Health Sciences, Biostatistics Section, University of Virginia, Charlottesville, VA 22908, USA.
27
Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA.
28
Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA.
29
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA.
30
A list of members and affiliations appears in the Supplemental Data.
31
Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA 02115, USA; Division of Sleep Medicine, Harvard Medical School, Boston, MA, 02115, USA; Division of Pulmonary, Critical Care and Sleep Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. Electronic address: sredline@bwh.harvard.edu.
32
Department of Population and Quantitative Health Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA. Electronic address: xxz10@case.edu.

Abstract

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.

KEYWORDS:

The Trans-Omics for Precision Medicine (TOPMed) program; arterial oxyhemoglobin saturation; linkage analysis; sleep-disordered breathing; whole-genome sequencing association analyses

PMID:
31668705
DOI:
10.1016/j.ajhg.2019.10.002

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