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; 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

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, 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

Department of Biomedical Sciences

Research output: Contribution to journal › Editorial › peer-review

61 Citations (Scopus)

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 language	English
Pages (from-to)	391-401
Number of pages	11
Journal	American Journal of Respiratory Cell and Molecular Biology
Volume	58
Issue number	3
DOIs	https://doi.org/10.1165/rcmb.2017-0237OC
Publication status	Published - 2018 Mar

Bibliographical note

Publisher Copyright:
Copyright © 2018 by the American Thoracic Society

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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10.1165/rcmb.2017-0237OC

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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., ... Redline, S. (2018). Multiethnic meta-analysis identifies RAI1 as a possible obstructive sleep apnea-related quantitative trait locus in men. American Journal of Respiratory Cell and Molecular Biology, 58(3), 391-401. https://doi.org/10.1165/rcmb.2017-0237OC

Chen, H, Cade, BE, Gleason, KJ, Bjonnes, AC, Stilp, AM, Sofer, T, Conomos, MP, Ancoli-Israel, S, Arens, R, Azarbarzin, A, Bell, GI, Below, JE, Chun, S, Evans, DS, Ewert, R, Frazier-Wood, AC, Gharib, SA, Haba-Rubio, J, Hagen, EW, Heinzer, R, Hillman, DR, Craig Johnson, W, Kutalik, Z, Lane, JM, Larkin, EK, Lee, SK, Liang, J, Loredo, JS, Mukherjee, S, Palmer, LJ, Papanicolaou, GJ, Penzel, T, Peppard, PE, Post, WS, Ramos, AR, Rice, K, Rotter, JI, Sands, SA, Shah, NA, Shin, C, Stone, KL, Stubbe, B, Sul, JH, Tafti, M, Taylor, KD, Teumer, A, Thornton, TA, Tranah, GJ, Wang, C, Wang, H, Warby, SC, Andrew Wellman, D, Zee, PC, Hanis, CL, Laurie, CC, Gottlieb, DJ, Patel, SR, Zhu, X, Sunyaev, SR, Saxena, R, Lin, X & Redline, S 2018, 'Multiethnic meta-analysis identifies RAI1 as a possible obstructive sleep apnea-related quantitative trait locus in men', American Journal of Respiratory Cell and Molecular Biology, vol. 58, no. 3, pp. 391-401. https://doi.org/10.1165/rcmb.2017-0237OC

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title = "Multiethnic meta-analysis identifies RAI1 as a possible obstructive sleep apnea-related quantitative trait locus in men",

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.",

keywords = "Genetics, Genome-wide association studies, Multiethnic, Obstructive sleep apnea, Sexual dimorphism",

author = "Han Chen and Cade, {Brian E.} and Gleason, {Kevin J.} and Bjonnes, {Andrew C.} and Stilp, {Adrienne M.} and Tamar Sofer and Conomos, {Matthew P.} and Sonia Ancoli-Israel and Raanan Arens and Ali Azarbarzin and Bell, {Graeme I.} and Below, {Jennifer E.} and Sung Chun and Evans, {Daniel S.} and Ralf Ewert and Frazier-Wood, {Alexis C.} and Gharib, {Sina A.} and Jos{\'e} Haba-Rubio and Hagen, {Erika W.} and Raphael Heinzer and Hillman, {David R.} and {Craig Johnson}, W. and Zoltan Kutalik and Lane, {Jacqueline M.} and Larkin, {Emma K.} and Lee, {Seung Ku} and Jingjing Liang and Loredo, {Jose S.} and Sutapa Mukherjee and Palmer, {Lyle J.} and Papanicolaou, {George J.} and Thomas Penzel and Peppard, {Paul E.} and Post, {Wendy S.} and Ramos, {Alberto R.} and Ken Rice and Rotter, {Jerome I.} and Sands, {Scott A.} and Shah, {Neomi A.} and Chol Shin and Stone, {Katie L.} and Beate Stubbe and Sul, {Jae Hoon} and Mehdi Tafti and Taylor, {Kent D.} and Alexander Teumer and Thornton, {Timothy A.} and Tranah, {Gregory J.} and Chaolong Wang and Heming Wang and Warby, {Simon C.} and {Andrew Wellman}, D. and Zee, {Phyllis C.} and Hanis, {Craig L.} and Laurie, {Cathy C.} and Gottlieb, {Daniel J.} and Patel, {Sanjay R.} and Xiaofeng Zhu and Sunyaev, {Shamil R.} and Richa Saxena and Xihong Lin and Susan Redline",

note = "Publisher Copyright: Copyright {\textcopyright} 2018 by the American Thoracic Society",

year = "2018",

month = mar,

doi = "10.1165/rcmb.2017-0237OC",

language = "English",

volume = "58",

pages = "391--401",

journal = "American Journal of Respiratory Cell and Molecular Biology",

issn = "1044-1549",

publisher = "American Thoracic Society",

number = "3",

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TY - JOUR

T1 - Multiethnic meta-analysis identifies RAI1 as a possible obstructive sleep apnea-related quantitative trait locus in men

AU - Chen, Han

AU - Cade, Brian E.

AU - Gleason, Kevin J.

AU - Bjonnes, Andrew C.

AU - Stilp, Adrienne M.

AU - Sofer, Tamar

AU - Conomos, Matthew P.

AU - Ancoli-Israel, Sonia

AU - Arens, Raanan

AU - Azarbarzin, Ali

AU - Bell, Graeme I.

AU - Below, Jennifer E.

AU - Chun, Sung

AU - Evans, Daniel S.

AU - Ewert, Ralf

AU - Frazier-Wood, Alexis C.

AU - Gharib, Sina A.

AU - Haba-Rubio, José

AU - Hagen, Erika W.

AU - Heinzer, Raphael

AU - Hillman, David R.

AU - Craig Johnson, W.

AU - Kutalik, Zoltan

AU - Lane, Jacqueline M.

AU - Larkin, Emma K.

AU - Lee, Seung Ku

AU - Liang, Jingjing

AU - Loredo, Jose S.

AU - Mukherjee, Sutapa

AU - Palmer, Lyle J.

AU - Papanicolaou, George J.

AU - Penzel, Thomas

AU - Peppard, Paul E.

AU - Post, Wendy S.

AU - Ramos, Alberto R.

AU - Rice, Ken

AU - Rotter, Jerome I.

AU - Sands, Scott A.

AU - Shah, Neomi A.

AU - Shin, Chol

AU - Stone, Katie L.

AU - Stubbe, Beate

AU - Sul, Jae Hoon

AU - Tafti, Mehdi

AU - Taylor, Kent D.

AU - Teumer, Alexander

AU - Thornton, Timothy A.

AU - Tranah, Gregory J.

AU - Wang, Chaolong

AU - Wang, Heming

AU - Warby, Simon C.

AU - Andrew Wellman, D.

AU - Zee, Phyllis C.

AU - Hanis, Craig L.

AU - Laurie, Cathy C.

AU - Gottlieb, Daniel J.

AU - Patel, Sanjay R.

AU - Zhu, Xiaofeng

AU - Sunyaev, Shamil R.

AU - Saxena, Richa

AU - Lin, Xihong

AU - Redline, Susan

PY - 2018/3

Y1 - 2018/3

N2 - 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.

AB - 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.

KW - Genetics

KW - Genome-wide association studies

KW - Multiethnic

KW - Obstructive sleep apnea

KW - Sexual dimorphism

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U2 - 10.1165/rcmb.2017-0237OC

DO - 10.1165/rcmb.2017-0237OC

M3 - Editorial

C2 - 29077507

AN - SCOPUS:85045223869

SN - 1044-1549

VL - 58

SP - 391

EP - 401

JO - American Journal of Respiratory Cell and Molecular Biology

JF - American Journal of Respiratory Cell and Molecular Biology

IS - 3

ER -

Multiethnic meta-analysis identifies RAI1 as a possible obstructive sleep apnea-related quantitative trait locus in men

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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