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 HeinzerDavid R. Hillman, W. Craig 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, D. Andrew 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, Susan Redline

Research output: Contribution to journalEditorialpeer-review

19 Scopus citations

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 languageEnglish (US)
Pages (from-to)391-401
Number of pages11
JournalAmerican journal of respiratory cell and molecular biology
Volume58
Issue number3
DOIs
StatePublished - 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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