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, Craig W 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, Andrew D 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, and Susan Redline. 2018. “Multiethnic Meta-Analysis Identifies RAI1 as a Possible Obstructive Sleep Apnea-related Quantitative Trait Locus in Men.” Am J Respir Cell Mol Biol, 58, 3, Pp. 391-401.


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.