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Meta-Analysis
. 2018 Mar;58(3):391-401.
doi: 10.1165/rcmb.2017-0237OC.

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

Han Chen  1   2   3 Brian E Cade  4   5 Kevin J Gleason  4   6 Andrew C Bjonnes  7   8 Adrienne M Stilp  9 Tamar Sofer  4   5   9 Matthew P Conomos  9 Sonia Ancoli-Israel  10 Raanan Arens  11 Ali Azarbarzin  4   5 Graeme I Bell  12 Jennifer E Below  2   13 Sung Chun  7   14 Daniel S Evans  15 Ralf Ewert  16 Alexis C Frazier-Wood  17 Sina A Gharib  18 José Haba-Rubio  19 Erika W Hagen  20 Raphael Heinzer  19 David R Hillman  21 W Craig Johnson  9 Zoltan Kutalik  22   23 Jacqueline M Lane  4   5   8   24 Emma K Larkin  25 Seung Ku Lee  26 Jingjing Liang  27 Jose S Loredo  28 Sutapa Mukherjee  29 Lyle J Palmer  30 George J Papanicolaou  31 Thomas Penzel  32 Paul E Peppard  20 Wendy S Post  33 Alberto R Ramos  34 Ken Rice  9 Jerome I Rotter  35 Scott A Sands  4   5 Neomi A Shah  36 Chol Shin  37 Katie L Stone  15 Beate Stubbe  16 Jae Hoon Sul  7   14   38 Mehdi Tafti  19   39 Kent D Taylor  35 Alexander Teumer  40 Timothy A Thornton  9 Gregory J Tranah  15 Chaolong Wang  1   41 Heming Wang  4   5   27 Simon C Warby  42 D Andrew Wellman  4   5 Phyllis C Zee  43 Craig L Hanis  2 Cathy C Laurie  9 Daniel J Gottlieb  4   5   44 Sanjay R Patel  45 Xiaofeng Zhu  27 Shamil R Sunyaev  7   14   24   46 Richa Saxena  4   5   8   24 Xihong Lin  1 Susan Redline  4   5   47
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Free PMC article
Meta-Analysis

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

Han Chen et al. Am J Respir Cell Mol Biol. .
Free PMC article

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.

Figures

Figure 1.
Figure 1.
Manhattan, quantile–quantile (Q-Q), and regional association plots of multiethnic meta-analysis results for apnea–hypopnea index during non–rapid eye movement sleep (AHI-N) in men. (A) The Manhattan plot shows −log10 P values against genomic coordinates (National Center for Biotechnology Information build 37), and consecutive chromosomes were colored in black and gray alternately. (B) The Q-Q plot shows observed −log10 P values against expected values under no association. (C) The regional association plot of multiethnic meta-analysis results for AHI-N in men near the RAI1 gene on chromosome 17.
Figure 2.
Figure 2.
Sex differences in the distribution of body mass index (BMI) and BMI2-adjusted residuals for study subjects with different genotypes (AA, AG, and GG) of rs12936587. The phenotype is rank-normalized sex-stratified residuals of apnea–hypopnea index during non–rapid eye movement sleep adjusting for age and age2. (A) Men and (B) women. AfA = African Americans; AsA = Asian Americans; EuA = European Americans; HsA = Hispanic/Latino Americans.

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