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Am J Respir Cell Mol Biol. 2018 Mar;58(3):391-401. doi: 10.1165/rcmb.2017-0237OC.

Multiethnic Meta-Analysis Identifies RAI1 as a Possible Obstructive Sleep Apnea-related Quantitative Trait Locus in Men.

Author information

1
1 Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.
2
2 Human Genetics Center, Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health and.
3
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
4 Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, Massachusetts.
5
5 Division of Sleep Medicine, Harvard Medical School, Boston, Massachusetts.
6
6 Department of Public Health Sciences, University of Chicago, Chicago, Illinois.
7
7 Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts.
8
8 Center for Genomic Medicine and Department of Anesthesia, Pain, and Critical Care Medicine, Massachusetts General Hospital, Boston, Massachusetts.
9
9 Department of Biostatistics, University of Washington, Seattle, Washington.
10
10 Departments of Medicine and Psychiatry, University of California, San Diego, California.
11
11 the Children's Hospital at Montefiore, Division of Respiratory and Sleep Medicine, Albert Einstein College of Medicine, Bronx, New York.
12
12 Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, the University of Chicago, Chicago, Illinois.
13
13 Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tennessee.
14
14 Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts.
15
15 California Pacific Medical Center Research Institute, San Francisco, California.
16
16 Internal Medicine B, University Medicine Greifswald, Greifswald, Germany.
17
17 Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas.
18
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
19 Center of Investigation and Research on Sleep, Lausanne University Hospital, Lausanne, Switzerland.
20
20 Department of Population Health Sciences, University of Wisconsin, Madison, Wisconsin.
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21 Department of Pulmonary Physiology and Sleep Medicine, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia.
22
22 Institute of Social and Preventive Medicine, University Hospital of Lausanne, Lausanne, Switzerland.
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23 Swiss Institute of Bioinformatics, Lausanne, Switzerland.
24
24 Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts.
25
25 Department of Medicine, Division of Allergy, Pulmonary, and Critical Care, Vanderbilt University Medical Center, Nashville, Tennessee.
26
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
27 Department of Epidemiology and Biostatistics, School of Medicine, Case Western Reserve University, Cleveland, Ohio.
28
28 Division of Pulmonary Critical Care and Sleep Medicine, Department of Medicine, University of California San Diego School of Medicine, La Jolla, California.
29
29 Adelaide Institute for Sleep Health, Flinders Centre of Research Excellence, Flinders University, Adelaide, South Australia, Australia.
30
30 School of Public Health, University of Adelaide, Adelaide, South Australia, Australia.
31
31 Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, Bethesda, Maryland.
32
32 University Hospital Charité Berlin, Sleep Center, Berlin, Germany.
33
33 Division of Cardiology, Johns Hopkins University, Baltimore, Maryland.
34
34 Department of Neurology, University of Miami Miller School of Medicine, Miami, Florida.
35
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
36 Division of Pulmonary, Critical Care, and Sleep, Icahn School of Medicine at Mount Sinai, New York, New York.
37
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
38 Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, California.
39
39 Department of Physiology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
40
40 Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
41
41 Computational and Systems Biology, Genome Institute of Singapore, Singapore.
42
42 Department of Psychiatry, University of Montreal, Montreal, Quebec, Canada.
43
43 Department of Neurology and Sleep Medicine Center, Northwestern University, Chicago, Illinois.
44
44 Veterans Affairs Boston Healthcare System, Boston, Massachusetts.
45
45 Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
46
46 Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts; and.
47
47 Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts.

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 × 10-8) 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.

KEYWORDS:

genetics; genome-wide association studies; multiethnic; obstructive sleep apnea; sexual dimorphism

PMID:
29077507
PMCID:
PMC5854957
[Available on 2019-03-01]
DOI:
10.1165/rcmb.2017-0237OC
[Indexed for MEDLINE]

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