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

Jingjing Liang; Brian E Cade; Karen Y He; Heming Wang; Jiwon Lee; Tamar Sofer; Stephanie Williams; Ruitong Li; Han Chen; Daniel J Gottlieb; Daniel S Evans; Xiuqing Guo; Sina A Gharib; Lauren Hale; David R Hillman; Pamela L Lutsey; Sutapa Mukherjee; Heather M Ochs-Balcom; Lyle J Palmer; Jessica Rhodes; Shaun Purcell; Sanjay R Patel; Richa Saxena; Katie L Stone; Weihong Tang; Gregory J Tranah; Eric Boerwinkle; Xihong Lin; Yongmei Liu; Bruce M Psaty; Ramachandran S Vasan; Michael H Cho; Ani Manichaikul; Edwin K Silverman; R Graham Barr; Stephen S Rich; Jerome I Rotter; James G Wilson; NHLBI Trans-Omics for Precision Medicine (TOPMed); TOPMed Sleep Working Group; Susan Redline; Xiaofeng Zhu

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

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

Authors

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.

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Chromosomes, Human, Pair 8 / genetics*
GTPase-Activating Proteins / genetics*
Genetic Linkage / genetics
Genome-Wide Association Study
Humans
Oxyhemoglobins / genetics*
Sleep / genetics*
Tumor Suppressor Proteins / genetics*
Whole Genome Sequencing / methods

Substances

DLC1 protein, human
GTPase-Activating Proteins
Oxyhemoglobins
Tumor Suppressor Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding