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

Han Chen; 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; Sina A Gharib; 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; Thomas Penzel; 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; Gregory J Tranah; 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

doi:10.1165/rcmb.2017-0237OC

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

Journal article

Open access

Peer reviewed

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

Han Chen, Brian E Cade, Kevin J Gleason, Andrew C Bjonnes, Adrienne M Stilp, Tamar Sofer, Matthew P Conomos, Sonia Ancoli-Israel, Raanan Arens, Ali Azarbarzin, …

American journal of respiratory cell and molecular biology, Vol.58(3), pp.391-401

2018-03

DOI: https://doi.org/10.1165/rcmb.2017-0237OC

PMCID: PMC5854957

PMID: 29077507

Abstract

ras Proteins - genetics

Genome-Wide Association Study

Sleep, REM - physiology

Humans

Middle Aged

Sleep Apnea, Obstructive - genetics

Male

Sex Characteristics

Transcription Factors - genetics

Phosphatidylethanolamine N-Methyltransferase - genetics

Sterol Regulatory Element Binding Protein 1 - genetics

Adult

Female

Aged

Quantitative Trait Loci - genetics

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.

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.137 Sleep Science & Circadian Systems; 1.137.382 Obstructive Sleep Apnea
Web Of Science research areas: Biochemistry & Molecular Biology; Cell Biology; Respiratory System
ESI research areas: Biology & Biochemistry

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Title: Multiethnic Meta-Analysis Identifies RAI1 as a Possible Obstructive Sleep Apnea-related Quantitative Trait Locus in Men
Creators: Han Chen - 3 Center for Precision Health, School of Public Health & School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, Texas
Brian E Cade - 5 Division of Sleep Medicine, Harvard Medical School, Boston, Massachusetts
Kevin J Gleason - 6 Department of Public Health Sciences, University of Chicago, Chicago, Illinois
Andrew C Bjonnes - 8 Center for Genomic Medicine and Department of Anesthesia, Pain, and Critical Care Medicine, Massachusetts General Hospital, Boston, Massachusetts
Adrienne M Stilp - 9 Department of Biostatistics, University of Washington, Seattle, Washington
Tamar Sofer - 9 Department of Biostatistics, University of Washington, Seattle, Washington
Matthew P Conomos - 9 Department of Biostatistics, University of Washington, Seattle, Washington
Sonia Ancoli-Israel - 10 Departments of Medicine and Psychiatry, University of California, San Diego, California
Raanan Arens - 11 the Children's Hospital at Montefiore, Division of Respiratory and Sleep Medicine, Albert Einstein College of Medicine, Bronx, New York
Ali Azarbarzin - 5 Division of Sleep Medicine, Harvard Medical School, Boston, Massachusetts
Graeme I Bell - 12 Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, the University of Chicago, Chicago, Illinois
Jennifer E Below - 13 Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tennessee
Sung Chun - 14 Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts
Daniel S Evans - 15 California Pacific Medical Center Research Institute, San Francisco, California
Ralf Ewert - 16 Internal Medicine B, University Medicine Greifswald, Greifswald, Germany
Alexis C Frazier-Wood - 17 Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas
Sina A Gharib - 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
José Haba-Rubio - 19 Center of Investigation and Research on Sleep, Lausanne University Hospital, Lausanne, Switzerland
Erika W Hagen - 20 Department of Population Health Sciences, University of Wisconsin, Madison, Wisconsin
Raphael Heinzer - 19 Center of Investigation and Research on Sleep, Lausanne University Hospital, Lausanne, Switzerland
David R Hillman - 21 Department of Pulmonary Physiology and Sleep Medicine, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia
W Craig Johnson - 9 Department of Biostatistics, University of Washington, Seattle, Washington
Zoltan Kutalik - 23 Swiss Institute of Bioinformatics, Lausanne, Switzerland
Jacqueline M Lane - 24 Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts
Emma K Larkin - 25 Department of Medicine, Division of Allergy, Pulmonary, and Critical Care, Vanderbilt University Medical Center, Nashville, Tennessee
Seung Ku Lee - 26 Institute of Human Genomic Study, College of Medicine, Korea University Ansan Hospital, Jeokgum-ro, Danwon-gu, Ansan-si, Gyeonggi-Do, Republic of Korea
Jingjing Liang - 27 Department of Epidemiology and Biostatistics, School of Medicine, Case Western Reserve University, Cleveland, Ohio
Jose S Loredo - 28 Division of Pulmonary Critical Care and Sleep Medicine, Department of Medicine, University of California San Diego School of Medicine, La Jolla, California
Sutapa Mukherjee - 29 Adelaide Institute for Sleep Health, Flinders Centre of Research Excellence, Flinders University, Adelaide, South Australia, Australia
Lyle J Palmer - 30 School of Public Health, University of Adelaide, Adelaide, South Australia, Australia
George J Papanicolaou - 31 Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, Bethesda, Maryland
Thomas Penzel - 32 University Hospital Charité Berlin, Sleep Center, Berlin, Germany
Paul E Peppard - 20 Department of Population Health Sciences, University of Wisconsin, Madison, Wisconsin
Wendy S Post - 33 Division of Cardiology, Johns Hopkins University, Baltimore, Maryland
Alberto R Ramos - 34 Department of Neurology, University of Miami Miller School of Medicine, Miami, Florida
Ken Rice - 9 Department of Biostatistics, University of Washington, Seattle, Washington
Jerome I Rotter - 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
Scott A Sands - 5 Division of Sleep Medicine, Harvard Medical School, Boston, Massachusetts
Neomi A Shah - 36 Division of Pulmonary, Critical Care, and Sleep, Icahn School of Medicine at Mount Sinai, New York, New York
Chol Shin - 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
Katie L Stone - 15 California Pacific Medical Center Research Institute, San Francisco, California
Beate Stubbe - 16 Internal Medicine B, University Medicine Greifswald, Greifswald, Germany
Jae Hoon Sul - 38 Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, California
Mehdi Tafti - 39 Department of Physiology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
Kent D Taylor - 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
Alexander Teumer - 40 Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
Timothy A Thornton - 9 Department of Biostatistics, University of Washington, Seattle, Washington
Gregory J Tranah - 15 California Pacific Medical Center Research Institute, San Francisco, California
Chaolong Wang - 41 Computational and Systems Biology, Genome Institute of Singapore, Singapore
Heming Wang - 27 Department of Epidemiology and Biostatistics, School of Medicine, Case Western Reserve University, Cleveland, Ohio
Simon C Warby - 42 Department of Psychiatry, University of Montreal, Montreal, Quebec, Canada
D Andrew Wellman - 5 Division of Sleep Medicine, Harvard Medical School, Boston, Massachusetts
Phyllis C Zee - 43 Department of Neurology and Sleep Medicine Center, Northwestern University, Chicago, Illinois
Craig L Hanis - 2 Human Genetics Center, Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health and
Cathy C Laurie - 9 Department of Biostatistics, University of Washington, Seattle, Washington
Daniel J Gottlieb - 44 Veterans Affairs Boston Healthcare System, Boston, Massachusetts
Sanjay R Patel - 45 Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
Xiaofeng Zhu - 27 Department of Epidemiology and Biostatistics, School of Medicine, Case Western Reserve University, Cleveland, Ohio
Shamil R Sunyaev - 46 Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts; and
Richa Saxena - 24 Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts
Xihong Lin - 1 Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
Susan Redline - 47 Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts
Publication Details: American journal of respiratory cell and molecular biology, Vol.58(3), pp.391-401
Grant note: KL2 TR000461 / NCATS NIH HHS R01 HL062252 / NHLBI NIH HHS N01HC95169 / NHLBI NIH HHS N01HC65235 / NHLBI NIH HHS R01 DK073541 / NIDDK NIH HHS HHSN268201100007C / NHLBI NIH HHS UL1 TR001881 / NCATS NIH HHS R01 HL085251 / NHLBI NIH HHS U01 AG042124 / NIA NIH HHS HHSN268201100005G / NHLBI NIH HHS U01 AG042139 / NIA NIH HHS N01HC95163 / NHLBI NIH HHS R01 HL070839 / NHLBI NIH HHS N01HC95166 / NHLBI NIH HHS R01 HL103612 / NHLBI NIH HHS R35 CA197449 / NCI NIH HHS HHSN268201100011C / NHLBI NIH HHS HHSN268201100011I / NHLBI NIH HHS R01 HL070847 / NHLBI NIH HHS HHSN268201100007I / NHLBI NIH HHS U01 AG042145 / NIA NIH HHS U01 HL053941 / NHLBI NIH HHS HHSN268201100010C / NHLBI NIH HHS HHSN268201100005C / NHLBI NIH HHS HHSN268201500003C / NHLBI NIH HHS R01 AR051124 / NIAMS NIH HHS N01HC25195 / NHLBI NIH HHS HHSN268201100005I / NHLBI NIH HHS UL1 TR000128 / NCATS NIH HHS R01 AI085014 / NIAID NIH HHS N01HC65233 / NHLBI NIH HHS N01HC85081 / NHLBI NIH HHS U01 AR066160 / NIAMS NIH HHS N01HC65236 / NHLBI NIH HHS N01HC95168 / NHLBI NIH HHS UL1 TR000040 / NCATS NIH HHS N01HC95165 / NHLBI NIH HHS P30 DK063491 / NIDDK NIH HHS R01 HL087652 / NHLBI NIH HHS N01HC95162 / NHLBI NIH HHS U01 AG042168 / NIA NIH HHS T32 HL007901 / NHLBI NIH HHS K01 HL135405 / NHLBI NIH HHS N01HC85086 / NHLBI NIH HHS U01 HL080295 / NHLBI NIH HHS U01 AG042143 / NIA NIH HHS R01 HL120393 / NHLBI NIH HHS R01 HL070848 / NHLBI NIH HHS N01HC95161 / NHLBI NIH HHS N01HC85083 / NHLBI NIH HHS HHSN268201100012C / NHLBI NIH HHS N01HC95164 / NHLBI NIH HHS P01 CA134294 / NCI NIH HHS R01 HL070837 / NHLBI NIH HHS HHSN268201100008I / NHLBI NIH HHS R01 HL070842 / NHLBI NIH HHS N01HC65237 / NHLBI NIH HHS N01HC95167 / NHLBI NIH HHS N02HL64278 / NHLBI NIH HHS N01HC85080 / NHLBI NIH HHS HHSN268201300005C / NHLBI NIH HHS R01 HL046380 / NHLBI NIH HHS N01HC95159 / NHLBI NIH HHS R01 AG023629 / NIA NIH HHS KL2 RR024990 / NCRR NIH HHS R01 DK107859 / NIDDK NIH HHS HHSN268201100006C / NHLBI NIH HHS R35 HL135818 / NHLBI NIH HHS UL1 TR001079 / NCATS NIH HHS UL1 TR000124 / NCATS NIH HHS P30 DK020595 / NIDDK NIH HHS U01 AG042140 / NIA NIH HHS P50 HL056984 / NHLBI NIH HHS HHSN268201200036C / NHLBI NIH HHS U01 HL130114 / NHLBI NIH HHS HHSN268200800007C / NHLBI NIH HHS N01HC55222 / NHLBI NIH HHS RC2 AR058973 / NIAMS NIH HHS R01 DK105072 / NIDDK NIH HHS N01HC85082 / NHLBI NIH HHS R01 HL070841 / NHLBI NIH HHS R01 HL102830 / NHLBI NIH HHS HHSN268201100008C / NHLBI NIH HHS N01HC65234 / NHLBI NIH HHS N01HC95160 / NHLBI NIH HHS R01 HL105756 / NHLBI NIH HHS U01 DK085501 / NIDDK NIH HHS UL1 TR000439 / NCATS NIH HHS HHSN268201100009C / NHLBI NIH HHS R01 HL070838 / NHLBI NIH HHS U01 AG027810 / NIA NIH HHS R01 HL071194 / NHLBI NIH HHS N01HC85079 / NHLBI NIH HHS HHSN268201100009I / NHLBI NIH HHS R01 HL113338 / NHLBI NIH HHS R21 AG056952 / NIA NIH HHS
Academic Unit: Miller School of Medicine; UMMG Department of Neurology
Language: English
Resource Type: Journal article
PMID: 29077507
PMCID: PMC5854957
Record Identifier: 991031597025502976