.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

Jingjing Liang¹, Brian E Cade², Karen Y He¹, Heming Wang², Jiwon Lee³, Tamar Sofer⁴, Stephanie Williams⁴, Ruitong Li⁴, Han Chen⁵, Daniel J Gottlieb⁶, Daniel S Evans⁷, Xiuqing Guo⁸, Sina A Gharib⁹, Lauren Hale¹⁰, David R Hillman¹¹, Pamela L Lutsey¹², Sutapa Mukherjee¹³, Heather M Ochs-Balcom¹⁴, Lyle J Palmer¹⁵, Jessica Rhodes¹⁶, Shaun Purcell², Sanjay R Patel¹⁷, Richa Saxena¹⁸, Katie L Stone⁷, Weihong Tang¹⁹, Gregory J Tranah⁷, Eric Boerwinkle²⁰, Xihong Lin²¹, Yongmei Liu²², Bruce M Psaty²³, Ramachandran S Vasan²⁴, Michael H Cho²⁵, Ani Manichaikul²⁶, Edwin K Silverman²⁵, R Graham Barr²⁷, Stephen S Rich²⁸, Jerome I Rotter⁸, James G Wilson²⁹; NHLBI Trans-Omics for Precision Medicine (TOPMed)³⁰; TOPMed Sleep Working Group³⁰; Susan Redline³¹, Xiaofeng Zhu³²

Affiliations

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.

PMID:31668705
PMCID: PMC6849112
DOI: 10.1016/j.ajhg.2019.10.002

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

Jingjing Liang et al. Am J Hum Genet.2019.

.2019 Nov 7;105(5):1057-1068.

doi: 10.1016/j.ajhg.2019.10.002. Epub 2019 Oct 24.

Authors

Affiliations

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.

PMID:31668705
PMCID: PMC6849112
DOI: 10.1016/j.ajhg.2019.10.002

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.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing interests.

Figures

**Figure 1**
Analysis Flow Chart for Searching Low-Frequency and Rare Variants Associated with AvSpO₂S

**Figure 2**
Linkage Evidence of AvSpO₂S on Chromosome 8 in Cleveland Family Study European Americans (A) LOD score in 8p23 linked to AvSpO₂S. The pink region is the 20 Mb target region in the sequencing analysis and the protein coding genes are presented in the bottom. (B) LOD score in 8p23 when the polygenic score (PS) of the 57 variants inDLC1 was included in the linkage analysis. The linkage curves are plotted with (red curve) and without (blue curve) adjusting for the PS. The gray curves are the 1,000 linkage curves adjusted for PS defined by 57 randomly selected frequency-matched variants outside of the target region (chr8: 21,780,000–146,302,000bp for GRCh37/hg19) on chromosome 8. The location ofDLC1 is marked with a black bar.

**Figure 3**
The 57 Variants inDLC1 (A) Cell-type-specific regulatory annotation enrichment tests for the 51 non-coding variants inDLC1 in 16 cell lines defined in the Ensemble Regulatory Build. The vertical dotted line represents the significance level after adjusting for multiple tests. (B) 51 non-coding variants and the corresponding effect sizes inDLC1 genes plotted against physical locations. The corresponding DNase hypersensitive, H3K4me3, H3K27ac, and CTCF elements derived from lung fibroblasts in the Encyclopedia of DNA Elements (ENCODE) data were also presented. (C). Association of the 57 variants inDLC1 withDLC1 expression level in 44 tissues from GTEx. The horizontal dotted line represents the significance level after adjustment for multiple tests. (D) Mendelian randomization analysis using the 24DLC1 variants as instrument variables.DLC1 expression level in skin-cell-transformed-fibroblasts in GTEx is treated as exposure and AvSpO₂S is treated as outcome. The solid red and blue dotted lines represent the causal effects estimated by the inverse-variance-weighted method and MR-Egger regression (see Supplemental Data).

See this image and copyright information in PMC

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

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

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