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Title: Multi-ethnic meta-analysis identifies RAI1 as a possible obstructive sleep apnea related quantitative trait locus in men

item CHEN, HAN - University Of Texas Health Science Center
item CADE, BRIAN - Brigham & Women'S Hospital
item GLEASON, KEVIN - University Of Chicago
item BJONNES, ANDREW - Brigham & Women'S Hospital
item STILP, ADRIENNE - University Of Washington
item SOFER, TAMAR - University Of Washington
item CONOMOS, MATTHEW - University Of Washington
item ANCOLI-ISRAEL, SONIA - University Of California
item ARENS, RAANAN - Albert Einstein College Of Medicine
item FRAZIER-WOOD, ALEXIS - Children'S Nutrition Research Center (CNRC)

Submitted to: American Journal of Respiratory Cell and Molecular Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/24/2017
Publication Date: 10/27/2017
Citation: Chen, H., Cade, B.E., Gleason, K.J., Bjonnes, A.C., Stilp, A.M., Sofer, T., Conomos, M.P., Ancoli-Israel, S., Arens, R., Azarbarzin, A., Bell, G.I., Below, J.E., Chun, S. Evans, D.S., Ewert, R., Frazier-Wood, A.C., Gharib, S.A., Haba-Rubio, J., Hagen, E. W., Heinzer, R., Hillman, D. R., Johnson, W.C., Kutalik, Z., Lane, J.M., Larkin, E.K., Lee, S.K., Liang, J., Loredo, J.S., Mukherjee, S., Palmer, L.J., Papanicolaou, G.J., Penzel, T., Peppard, P.E., Post, W.S., Ramos, A. R., Rice, K., Rotter, J. I., Sands, S.A., Shah, N.A., Shin,C., Stone, K.L., Stubbe, B., Sul, J.H., Tafti, M., Taylor, K.D., Teumer, A., Thornton, T.A., Tranah, G.J., Wang, C., Wang, H., Warby, S.C., Wellman, D.A., Zee, P.C., Hanis, C.L., Laurie, C.C., Gottlieb, D.J., Patel, S.R., Zhu, X., Sunyaev, S.R., Saxena, R., Lin, X., Redline, S. 2017. Multi-ethnic meta-analysis identifies RAI1 as a possible obstructive sleep apnea related quantitative trait locus in men. American Journal of Respiratory Cell and Molecular Biology.

Interpretive Summary: Obesity is associated with poorer sleep, and obstructive sleep apnea (OSA) is a common disorder more common in those with overweight and obesity. Not all individuals with obesity will go on to develop OSA. Since OSA is heritable, identifying which genes increase the risk for OSA might help identify those individuals where having excess body weight puts them at increased risk for OSA. The problem is that we don't know which genes influence OSA. To address this problem, we used genetic and sleep study data from 19,733 adults, and identified a new locus influencing OSA in men, but not women. This information is useful for clinicians who may wish to identify which people with excess body weight are at risk of OSA, which will help them better target prevention and treatment options, and so be able to better reduce the negative sequelae associated with increasing weight status.

Technical 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. Since 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 multi-ethnic samples. We performed genome-wide association tests for up to 19,733 participants of African-, Asian-, European-, and Hispanic/Latino-American ancestry in seven 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.