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

Am J Respir Cell Mol Biol. 2018 Mar;58(3):391-401. doi: 10.1165/rcmb.2017-0237OC.

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.

Keywords: genetics; genome-wide association studies; multiethnic; obstructive sleep apnea; sexual dimorphism.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Trans-Activators
  • Transcription Factors / genetics*
  • ras Proteins / genetics

Substances

  • RAI1 protein, human
  • RASD1 protein, human
  • SREBF1 protein, human
  • Sterol Regulatory Element Binding Protein 1
  • Trans-Activators
  • Transcription Factors
  • PEMT protein, human
  • Phosphatidylethanolamine N-Methyltransferase
  • ras Proteins

Grant support