Multiethnic Meta-Analysis Identifies RAI1 as a Possible Obstructive Sleep Apnea-related Quantitative Trait Locus in Men.
Gregory J Tranah, Paul E Peppard, Wendy S Post, Alberto R Ramos, Ken Rice, Jerome I Rotter, Scott A Sands, Neomi A Shah, Chol Shin, Katie L Stone, Beate Stubbe, Jae Hoon Sul, Mehdi Tafti, Kent D Taylor, Alexander Teumer, Timothy A Thornton, Thomas Penzel, Chaolong Wang, Heming Wang, Simon C Warby, D Andrew Wellman, Phyllis C Zee, Craig L Hanis, Cathy C Laurie, Daniel J Gottlieb, Sanjay R Patel, Xiaofeng Zhu, Shamil R Sunyaev, Richa Saxena, Xihong Lin, Susan Redline, Sina A Gharib, Brian E Cade, Kevin J Gleason, Andrew C Bjonnes, Adrienne M Stilp, Tamar Sofer, Matthew P Conomos, Sonia Ancoli-Israel, Raanan Arens, Ali Azarbarzin, Graeme I Bell, Jennifer E Below, Sung Chun, Daniel S Evans, Ralf Ewert, Alexis C Frazier-Wood, Han Chen, José Haba-Rubio, Erika W Hagen, Raphael Heinzer, David R Hillman, W Craig Johnson, Zoltan Kutalik, Jacqueline M Lane, Emma K Larkin, Seung Ku Lee, Jingjing Liang, Jose S Loredo, Sutapa Mukherjee, Lyle J Palmer, George J Papanicolaou
Journal: American journal of respiratory cell and molecular biology
2018;58(3):391-401
PMID: 29077507
Abstract
Obstructive sleep apnea (OSA) is a common heritable disorder displaying marked sexual dimorphism in disease prevalence and progression. Previous genetic association studies have identified a few genetic loci associated with OSA and related quantitative traits, but they have only focused on single ethnic groups, and a large proportion of the heritability remains unexplained. The apnea-hypopnea index (AHI) is a commonly used quantitative measure characterizing OSA severity. Because OSA differs by sex, and the pathophysiology of obstructive events differ in rapid eye movement (REM) and non-REM (NREM) sleep, we hypothesized that additional genetic association signals would be identified by analyzing the NREM/REM-specific AHI and by conducting sex-specific analyses in multiethnic samples. We performed genome-wide association tests for up to 19,733 participants of African, Asian, European, and Hispanic/Latino American ancestry in 7 studies. We identified rs12936587 on chromosome 17 as a possible quantitative trait locus for NREM AHI in men (N = 6,737; P = 1.7 × 10) but not in women (P = 0.77). The association with NREM AHI was replicated in a physiological research study (N = 67; P = 0.047). This locus overlapping the RAI1 gene and encompassing genes PEMT1, SREBF1, and RASD1 was previously reported to be associated with coronary artery disease, lipid metabolism, and implicated in Potocki-Lupski syndrome and Smith-Magenis syndrome, which are characterized by abnormal sleep phenotypes. We also identified gene-by-sex interactions in suggestive association regions, suggesting that genetic variants for AHI appear to vary by sex, consistent with the clinical observations of strong sexual dimorphism.
Address:
1 Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.; 2 Human Genetics Center, Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health and.; 3 Center for Precision Health, School of Public Health & School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, Texas.; 4 Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, Massachusetts.; 5 Division of Sleep Medicine, Harvard Medical School, Boston, Massachusetts.; 6 Department of Public Health Sciences, University of Chicago, Chicago, Illinois.; 7 Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts.; 8 Center for Genomic Medicine and Department of Anesthesia, Pain, and Critical Care Medicine, Massachusetts General Hospital, Boston, Massachusetts.; 9 Department of Biostatistics, University of Washington, Seattle, Washington.; 10 Departments of Medicine and Psychiatry, University of California, San Diego, California.; 11 the Children's Hospital at Montefiore, Division of Respiratory and Sleep Medicine, Albert Einstein College of Medicine, Bronx, New York.; 12 Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, the University of Chicago, Chicago, Illinois.; 13 Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tennessee.; 14 Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts.; 15 California Pacific Medical Center Research Institute, San Francisco, California.; 16 Internal Medicine B, University Medicine Greifswald, Greifswald, Germany.; 17 Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas.; 18 Computational Medicine Core, Center for Lung Biology, University of Washington Medicine Sleep Center, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Washington, Seattle, Washington.; 19 Center of Investigation and Research on Sleep, Lausanne University Hospital, Lausanne, Switzerland.; 20 Department of Population Health Sciences, University of Wisconsin, Madison, Wisconsin.; 21 Department of Pulmonary Physiology and Sleep Medicine, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia.; 22 Institute of Social and Preventive Medicine, University Hospital of Lausanne, Lausanne, Switzerland.; 23 Swiss Institute of Bioinformatics, Lausanne, Switzerland.; 24 Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts.; 25 Department of Medicine, Division of Allergy, Pulmonary, and Critical Care, Vanderbilt University Medical Center, Nashville, Tennessee.; 26 Institute of Human Genomic Study, College of Medicine, Korea University Ansan Hospital, Jeokgum-ro, Danwon-gu, Ansan-si, Gyeonggi-Do, Republic of Korea.; 27 Department of Epidemiology and Biostatistics, School of Medicine, Case Western Reserve University, Cleveland, Ohio.; 28 Division of Pulmonary Critical Care and Sleep Medicine, Department of Medicine, University of California San Diego School of Medicine, La Jolla, California.; 29 Adelaide Institute for Sleep Health, Flinders Centre of Research Excellence, Flinders University, Adelaide, South Australia, Australia.; 30 School of Public Health, University of Adelaide, Adelaide, South Australia, Australia.; 31 Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, Bethesda, Maryland.; 32 University Hospital Charité Berlin, Sleep Center, Berlin, Germany.; 33 Division of Cardiology, Johns Hopkins University, Baltimore, Maryland.; 34 Department of Neurology, University of Miami Miller School of Medicine, Miami, Florida.; 35 Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute and Department of Pediatrics at Harbor-University of California Los Angeles Medical Center, Torrance, California.; 36 Division of Pulmonary, Critical Care, and Sleep, Icahn School of Medicine at Mount Sinai, New York, New York.; 37 Department of Pulmonary, Sleep, and Critical Care Medicine, College of Medicine, Korea University Ansan Hospital, Jeokgum-ro, Danwon-gu, Ansan-si, Gyeonggi-do, Republic of Korea.; 38 Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, California.; 39 Department of Physiology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.; 40 Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.; 41 Computational and Systems Biology, Genome Institute of Singapore, Singapore.; 42 Department of Psychiatry, University of Montreal, Montreal, Quebec, Canada.; 43 Department of Neurology and Sleep Medicine Center, Northwestern University, Chicago, Illinois.; 44 Veterans Affairs Boston Healthcare System, Boston, Massachusetts.; 45 Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.; 46 Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts; and.; 47 Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
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MeSH Terms:
Adult,
Aged,
Female,
Genome-Wide Association Study,
Humans,
Male,
Middle Aged,
Phosphatidylethanolamine N-Methyltransferase,
Quantitative Trait Loci,
Sex Characteristics,
Sleep Apnea, Obstructive,
Sleep, REM,
Sterol Regulatory Element Binding Protein 1,
Trans-Activators,
Transcription Factors,
ras Proteins