학술논문
Multiethnic Meta-Analysis Identifies RAI1 as a Possible Obstructive Sleep Apnea–related Quantitative Trait Locus in Men
Document Type
article
Author
Chen, Han; Cade, Brian E; Gleason, Kevin J; Bjonnes, Andrew C; Stilp, Adrienne M; Sofer, Tamar; Conomos, Matthew P; Ancoli-Israel, Sonia; Arens, Raanan; Azarbarzin, Ali; Bell, Graeme I; Below, Jennifer E; Chun, Sung; Evans, Daniel S; Ewert, Ralf; Frazier-Wood, Alexis C; Gharib, Sina A; Haba-Rubio, José; Hagen, Erika W; Heinzer, Raphael; Hillman, David R; Johnson, W Craig; Kutalik, Zoltan; Lane, Jacqueline M; Larkin, Emma K; Lee, Seung Ku; Liang, Jingjing; Loredo, Jose S; Mukherjee, Sutapa; Palmer, Lyle J; Papanicolaou, George J; Penzel, Thomas; Peppard, Paul E; Post, Wendy S; Ramos, Alberto R; Rice, Ken; Rotter, Jerome I; Sands, Scott A; Shah, Neomi A; Shin, Chol; Stone, Katie L; Stubbe, Beate; Sul, Jae Hoon; Tafti, Mehdi; Taylor, Kent D; Teumer, Alexander; Thornton, Timothy A; Tranah, Gregory J; Wang, Chaolong; Wang, Heming; Warby, Simon C; Wellman, D Andrew; Zee, Phyllis C; Hanis, Craig L; Laurie, Cathy C; Gottlieb, Daniel J; Patel, Sanjay R; Zhu, Xiaofeng; Sunyaev, Shamil R; Saxena, Richa; Lin, Xihong; Redline, Susan
Source
American Journal of Respiratory Cell and Molecular Biology. 58(3)
Subject
Language
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.