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 genomewide 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 3 1028) 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 391-401 |
| Number of pages | 11 |
| Journal | American journal of respiratory cell and molecular biology |
| Volume | 58 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 2018 |
Keywords
- Genetics
- Genome-wide association studies
- Multiethnic
- Obstructive sleep apnea
- Sexual dimorphism
ASJC Scopus subject areas
- Molecular Biology
- Pulmonary and Respiratory Medicine
- Clinical Biochemistry
- Cell Biology
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In: American journal of respiratory cell and molecular biology, Vol. 58, No. 3, 03.2018, p. 391-401.
Research output: Contribution to journal › Editorial › peer-review
}
TY - JOUR
T1 - Multiethnic meta-analysis identifies RAI1 as a possible obstructive sleep apnea-related quantitative trait locus in men
AU - Chen, Han
AU - Cade, Brian E.
AU - Gleason, Kevin J.
AU - Bjonnes, Andrew C.
AU - Stilp, Adrienne M.
AU - Sofer, Tamar
AU - Conomos, Matthew P.
AU - Ancoli-Israel, Sonia
AU - Arens, Raanan
AU - Azarbarzin, Ali
AU - Bell, Graeme I.
AU - Below, Jennifer E.
AU - Chun, Sung
AU - Evans, Daniel S.
AU - Ewert, Ralf
AU - Frazier-Wood, Alexis C.
AU - Gharib, Sina A.
AU - Haba-Rubio, José
AU - Hagen, Erika W.
AU - Heinzer, Raphael
AU - Hillman, David R.
AU - Craig Johnson, W.
AU - Kutalik, Zoltan
AU - Lane, Jacqueline M.
AU - Larkin, Emma K.
AU - Lee, Seung Ku
AU - Liang, Jingjing
AU - Loredo, Jose S.
AU - Mukherjee, Sutapa
AU - Palmer, Lyle J.
AU - Papanicolaou, George J.
AU - Penzel, Thomas
AU - Peppard, Paul E.
AU - Post, Wendy S.
AU - Ramos, Alberto R.
AU - Rice, Ken
AU - Rotter, Jerome I.
AU - Sands, Scott A.
AU - Shah, Neomi A.
AU - Shin, Chol
AU - Stone, Katie L.
AU - Stubbe, Beate
AU - Sul, Jae Hoon
AU - Tafti, Mehdi
AU - Taylor, Kent D.
AU - Teumer, Alexander
AU - Thornton, Timothy A.
AU - Tranah, Gregory J.
AU - Wang, Chaolong
AU - Wang, Heming
AU - Warby, Simon C.
AU - Andrew Wellman, D.
AU - Zee, Phyllis C.
AU - Hanis, Craig L.
AU - Laurie, Cathy C.
AU - Gottlieb, Daniel J.
AU - Patel, Sanjay R.
AU - Zhu, Xiaofeng
AU - Sunyaev, Shamil R.
AU - Saxena, Richa
AU - Lin, Xihong
AU - Redline, Susan
N1 - Funding Information: This work was supported by National Institutes of Health (NIH) grants R01-HL113338, P01-CA134294, and R35-CA197449 (H.C.), T32-HL007901 and R01-HL113338 (B.E.C.), and R01-HL113338 and R35-HL135818 (S.R.). The Sleep Reading Center of Brigham and Women’s Hospital was supported by NIH grants 5-R01-HL046380-15 and 5-KL2-RR024990-05; the Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute (NHLBI) contracts HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C; the Framingham Heart Study is conducted and supported by NHLBI in collaboration with Boston University contract N01-HC-25195; funding for SHARe Affymetrix genotyping was provided by NHLBI contract N02-HL-64278; SHARe Illumina genotyping was provided under an agreement between Illumina and Boston University; funding support for the Framingham Sleep Heart Health Study was provided by NIH/NHLBI grant U01 HL 53941; the baseline examination of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) was carried out as a collaborative study supported by contracts from the NHLBI to the University of North Carolina (N01-HC65233), University of Miami (N01-HC65234), Albert Einstein College of Medicine (N01-HC65235), Northwestern University (N01-HC65236), and San Diego State University (N01-HC65237). The following institutes/centers/offices contributed to the first phase of HCHS/SOL through a transfer of funds to the NHLBI: National Institute on Minority Health and Health Disparities, National Institute on Deafness and Other Communication Disorders, National Institute of Dental and Craniofacial Research (NIDCR), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Neurological Disorders and Stroke (NINDS), and NIH Institution-Office of Dietary Supplements. The Genetic Analysis Center at the University of Washington was supported by NHLBI and NIDCR contracts HHSN268201300005C AM03 and MOD03. Provision of genotyping services was supported in part by the National Center for Advancing Translational Sciences (NCATS) Clinical and Translational Science Institute (CTSI) grant UL1TR000124 and NIDDK Diabetes Research Center (DRC) grant DK063491. The Multi-Ethnic Study of Atherosclerosis (MESA) is conducted and supported by the NHLBI in collaboration with MESA investigators, and was supported by contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169 from the NHLBI and by grants UL1-TR-000040 and UL1-TR-001079 from National Center for Research Resources (NCRR). Funding for SHARe genotyping was provided by NHLBI contract N02-HL-64278. Genotyping was performed at Affymetrix and the Broad Institute of Harvard and Massachusetts Institute of Technology. Funding support for the Sleep Polysomnography dataset was provided by NHLBI grant HL56984. Provision of genotyping services supported in part by NCATS CTSI grant UL1TR000124 and NIDDK DRC grant DK063491. The Osteoporotic Fractures in Men Study (MrOS) is supported by NIH funding. The following institutes provide support: the National Institute on Aging (NIA), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NCATS, and NIH Roadmap for Medical Research under grants U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160, and UL1 TR000128. The NHLBI provides funding for the MrOS Sleep ancillary study “Outcomes of Sleep Disorders in Older Men” under grants R01 HL071194, R01 HL070848, R01 HL070847, R01 HL070842, R01 HL070841, R01 HL070837, R01 HL070838, and R01 HL070839. The NIAMS provides funding for the MrOS ancillary study “Replication of candidate gene associations and bone strength phenotype in MrOS” under grant R01 AR051124. The NIAMS provides funding for the MrOS ancillary study “GWAS in MrOS and SOF” under grant RC2 AR058973. The Starr County Health Studies are supported in part by NIH grants R01 DK073541, U01 DK085501, R01 AI085014, and R01 HL102830, and funds from The University of Texas Health Science Center at Houston. G.I.B. was supported in part by grant P30 DK020595 and a gift from the Kovler Family Foundation. The KoGES_Ansan study was provided with biospecimens and data from the Korean Genome Analysis Project (4845-301), the Korean Genome and Epidemiology Study (2009-E71002-00, 2010-E71001-00, 2011-E71004-00, 2012-E71005-00, 2013-E71005-00, and 2014-E71003-00), and Korea Biobank Project (4851-307) that were supported by the Korea Centers for Disease Control & Prevention, Republic of Korea. The Cardiovascular Health Study research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393, and R01HL130114, with additional contribution from NINDS. Genotyping among the African American cohort was supported in part by HL085251 from NHLBI. Additional support was provided through NIA grant R01AG023629. The provision of genotyping data was supported in part by NCATS CTSI grant UL1TR000124 and NIDDK DRC grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The HypnoLaus and CoLaus/HypnoLaus study was supported by research grants from GlaxoSmithKline, the Faculty of Biology and Medicine of Lausanne, the Swiss National Science Foundation grants 3200B0-105993, 3200B0-118308, 33CSCO-122661, 33CS30-139468, and 33CS30-148401, the Leenaards Foundation, and the Vaud Pulmonary League (Ligue Pulmonaire Vaudoise). The Study of Health in Pomerania is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by Federal Ministry of Education and Research grants 01ZZ9603, 01ZZ0103, and 01ZZ0403, Competence Network Asthma/ COPD grant FKZ 01GI0881-0888, the Ministry of Cultural Affairs, as well as the Social Ministry of the Federal State of Mecklenburg–West Pomerania, and the network “Greifswald Approach to Individualized Medicine” funded by Federal Ministry of Education and Research grant 03IS2061A. The polysomnography was additionally funded by the German Restless Legs Association. Funding for the Western Australian Sleep Health Study was obtained from the Sir Charles Gairdner and Hollywood Private Hospital Research Foundations, the Western Australian Sleep Disorders Research Institute, and the Centre for Genetic Epidemiology and Biostatistics at the University of Western Australia. Funding for the genome-wide association studies (GWAS) genotyping was obtained from the Ontario Institute for Cancer Research and a McLaughlin Centre Accelerator Grant from the University of Toronto. The Wisconsin Sleep Cohort (WSC) Study phenotype data collection was supported by NIH grants R01HL62252 and 1UL1RR02501. GWAS typing of the WSC was conducted thanks to private donations and NIH-23724 to Dr. Emmanuel Mignot, Psychiatry and Behavioral Sciences, Stanford Center for Sleep Sciences and Medicine. Publisher Copyright: Copyright © 2018 by the American Thoracic Society
PY - 2018/3
Y1 - 2018/3
N2 - 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 genomewide 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 3 1028) 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.
AB - 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 genomewide 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 3 1028) 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.
KW - Genetics
KW - Genome-wide association studies
KW - Multiethnic
KW - Obstructive sleep apnea
KW - Sexual dimorphism
UR - http://www.scopus.com/inward/record.url?scp=85045223869&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85045223869&partnerID=8YFLogxK
U2 - 10.1165/rcmb.2017-0237OC
DO - 10.1165/rcmb.2017-0237OC
M3 - Editorial
C2 - 29077507
AN - SCOPUS:85045223869
SN - 1044-1549
VL - 58
SP - 391
EP - 401
JO - American journal of respiratory cell and molecular biology
JF - American journal of respiratory cell and molecular biology
IS - 3
ER -