Journal Article

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

Katie L. Stone, Sutapa Mukherjee, Alexander Teumer, Neomi A. Shah, Jingjing Liang, Jacqueline M. Lane, Shamil R. Sunyaev, Sung Chun, Jerome I. Rotter, Han Chen, Daniel J. Gottlieb, Paul E. Peppard, Sonia Ancoli-Israel, Kenneth Rice, Seung Ku Lee, George J. Papanicolaou, Erika W. Hagen, Xiaofeng Zhu, Wendy S. Post, Chaolong Wang, Adrienne M. Stilp, Jennifer E. Below, Jose S. Loredo, Raphael Heinzer, Daniel S. Evans, Ralf Ewert, Ali Azarbarzin, Beate Stubbe, Andrew Bjonnes, Sina A. Gharib, Zoltán Kutalik, Phyllis C. Zee, Thomas Penzel, Cathy C. Laurie, Timothy A. Thornton, Sanjay R. Patel, D. Andrew Wellman, Scott A. Sands, Tamar Sofer, Gregory J. Tranah, Matthew P. Conomos, José Haba-Rubio, Richa Saxena, Graeme I. Bell, Mehdi Tafti, Alberto R. Ramos, Craig L. Hanis, Xihong Lin, Raanan Arens, Lyle J. Palmer, Chol Shin, Kevin J. Gleason, Alexis C. Frazier-Wood, W. Craig Johnson, Heming Wang, Susan Redline, Kent D. Taylor, Simon C. Warby, Jae Hoon Sul, Emma K. Larkin, Brian E. Cade, David R. Hillman

2018

Overview

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.

• Publisher: American Thoracic Society,Oxford University Press
• Subject: 2.1 Biological and endogenous factors / Adult / Adult; Aged; Female; Genome-Wide Association Study; Humans; Male; Middle Aged; Phosphatidylethanolamine N-Methyltransferase/genetics; Quantitative Trait Loci/genetics; Sex Characteristics; Sleep Apnea, Obstructive/genetics; Sleep, REM/physiology; Sterol Regulatory Element Binding Protein 1/genetics; Transcription Factors/genetics; ras Proteins/genetics; genetics; genome-wide association studies; multiethnic; obstructive sleep apnea; sexual dimorphism / Aetiology / African Americans / Aged / Apnea / Asian Americans / Atherosclerosis / Biochemistry and cell biology / Biological Sciences / Biomedical and Clinical Sciences / Body mass index / Cardiorespiratory Medicine and Haematology / Cardiovascular disease / Cardiovascular medicine and haematology / Chromosome 17 / Chronic fatigue syndrome / Clinical Research / Consortia / Coronary artery / Coronary vessels / Ethnic studies / Eye movements / Female / Gender differences / Gene loci / Genetic diversity / Genetics / genome-wide association studies / Genome-Wide Association Study / Genomes / Genomics / Heart diseases / Heritability / Hispanic Americans / Human Genome / Humans / Lipid metabolism / Lipids / Lung / Male / Mens health / Meta-analysis / Metabolism / Middle Aged / Minority & ethnic groups / multiethnic / NREM sleep / Obstructive / obstructive sleep apnea / Original Research / Phosphatidylethanolamine N-Methyltransferase / Phosphatidylethanolamine N-Methyltransferase - genetics / Physiology / Quantitative Trait Loci / Quantitative Trait Loci - genetics / ras Proteins / ras Proteins - genetics / REM / REM sleep / Respiratory System / Sex / Sex Characteristics / Sexual dimorphism / Sleep / Sleep Apnea / Sleep Apnea, Obstructive / Sleep Apnea, Obstructive - genetics / Sleep disorders / Sleep Research / Sleep, REM / Sleep, REM - physiology / Sterol Regulatory Element Binding Protein 1 / Sterol Regulatory Element Binding Protein 1 - genetics / Studies / Trans-Activators / Transcription Factors / Transcription Factors - genetics / Womens health