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

TitleMultiethnic Meta-Analysis Identifies RAI1 as a Possible Obstructive Sleep Apnea-related Quantitative Trait Locus in Men.
Publication TypePublication
Year2018
AuthorsChen H, Cade BE, Gleason KJ, Bjonnes AC, Stilp AM, Sofer T, Conomos MP, Ancoli-Israel S, Arens R, Azarbarzin A, Bell GI, Below JE, Chun S, Evans DS, Ewert R, Frazier-Wood AC, Gharib SA, Haba-Rubio J, Hagen EW, Heinzer R, Hillman DR, W Johnson C, Kutalik Z, Lane JM, Larkin EK, Lee SKu, Liang J, Loredo JS, Mukherjee S, Palmer LJ, Papanicolaou GJ, Penzel T, Peppard PE, Post WS, Ramos AR, Rice K, Rotter JI, Sands SA, Shah NA, Shin C, Stone KL, Stubbe B, Sul JHoon, Tafti M, Taylor KD, Teumer A, Thornton TA, Tranah GJ, Wang C, Wang H, Warby SC, D Wellman A, Zee PC, Hanis CL, Laurie CC, Gottlieb DJ, Patel SR, Zhu X, Sunyaev SR, Saxena R, Lin X, Redline S
JournalAm J Respir Cell Mol Biol
Volume58
Issue3
Pagination391-401
Date Published2018 03
ISSN1535-4989
KeywordsAdult, Aged, Female, genome-wide association study, Humans, Male, Middle Aged, Phosphatidylethanolamine N-Methyltransferase, Quantitative Trait Loci, ras Proteins, Sex Characteristics, Sleep Apnea, Obstructive, Sleep, REM, Sterol Regulatory Element Binding Protein 1, Trans-Activators, Transcription Factors
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.

DOI10.1165/rcmb.2017-0237OC
Alternate JournalAm J Respir Cell Mol Biol
PubMed ID29077507
PubMed Central IDPMC5854957
Grant ListU01 DK085501 / DK / NIDDK NIH HHS / United States
HHSN268201100012C / HL / NHLBI NIH HHS / United States
R01 HL103612 / HL / NHLBI NIH HHS / United States
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MS#: 
0476
Manuscript Lead/Corresponding Author Affiliation: 
HCHS/SOL Baseline Visit - Sleep Center - Harvard Medical School/The Brigham & Women's Hospital
ECI: 
Yes
Manuscript Status: 
Published