Whole-genome association analyses of sleep-disordered breathing phenotypes in the NHLBI TOPMed program

Brian E. Cade; Jiwon Lee; Tamar Sofer; Heming Wang; Man Zhang; Han Chen; Sina A. Gharib; Daniel J. Gottlieb; Xiuqing Guo; Jacqueline M. Lane; Jingjing Liang; Xihong Lin; Hao Mei; Sanjay R. Patel; Shaun M. Purcell; Richa Saxena; Neomi A. Shah; Daniel S. Evans; Craig L. Hanis; David R. Hillman; Sutapa Mukherjee; Lyle J. Palmer; Katie L. Stone; Gregory J. Tranah; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium; Gonçalo R. Abecasis; Eric A. Boerwinkle; Adolfo Correa; Robert C. Kaplan; L. Adrienne Cupples; Deborah A. Nickerson; Kari E. North; Bruce M. Psaty; Jerome I. Rotter; Stephen S. Rich; Russell P. Tracy; Ramachandran S. Vasan; James G. Wilson; Xiaofeng Zhu; Susan Redline; TOPMed Sleep Working Group

doi:10.1186/s13073-021-00917-8

Whole-genome association analyses of sleep-disordered breathing phenotypes in the NHLBI TOPMed program

Brian E. Cade, Jiwon Lee, Tamar Sofer, Heming Wang, Man Zhang, Han Chen, Sina A. Gharib, Daniel J. Gottlieb, Xiuqing Guo, Jacqueline M. Lane, Jingjing Liang, Xihong Lin, Hao Mei, Sanjay R. Patel, Shaun M. Purcell, Richa Saxena, Neomi A. Shah, Daniel S. Evans, Craig L. Hanis, David R. HillmanSutapa Mukherjee, Lyle J. Palmer, Katie L. Stone, Gregory J. Tranah, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Gonçalo R. Abecasis, Eric A. Boerwinkle, Adolfo Correa, Robert C. Kaplan, L. Adrienne Cupples, Deborah A. Nickerson, Kari E. North, Bruce M. Psaty, Jerome I. Rotter, Stephen S. Rich, Russell P. Tracy, Ramachandran S. Vasan, James G. Wilson, Xiaofeng Zhu, Susan Redline, TOPMed Sleep Working Group

College of Medicine and Public Health

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

21 Citations (Scopus)

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Abstract

Background: Sleep-disordered breathing is a common disorder associated with significant morbidity. The genetic architecture of sleep-disordered breathing remains poorly understood. Through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program, we performed the first whole-genome sequence analysis of sleep-disordered breathing. Methods: The study sample was comprised of 7988 individuals of diverse ancestry. Common-variant and pathway analyses included an additional 13,257 individuals. We examined five complementary traits describing different aspects of sleep-disordered breathing: the apnea-hypopnea index, average oxyhemoglobin desaturation per event, average and minimum oxyhemoglobin saturation across the sleep episode, and the percentage of sleep with oxyhemoglobin saturation < 90%. We adjusted for age, sex, BMI, study, and family structure using MMSKAT and EMMAX mixed linear model approaches. Additional bioinformatics analyses were performed with MetaXcan, GIGSEA, and ReMap. Results: We identified a multi-ethnic set-based rare-variant association (p = 3.48 × 10 ⁻⁸) on chromosome X with ARMCX3. Additional rare-variant associations include ARMCX3-AS1, MRPS33, and C16orf90. Novel common-variant loci were identified in the NRG1 and SLC45A2 regions, and previously associated loci in the IL18RAP and ATP2B4 regions were associated with novel phenotypes. Transcription factor binding site enrichment identified associations with genes implicated with respiratory and craniofacial traits. Additional analyses identified significantly associated pathways. Conclusions: We have identified the first gene-based rare-variant associations with objectively measured sleep-disordered breathing traits. Our results increase the understanding of the genetic architecture of sleep-disordered breathing and highlight associations in genes that modulate lung development, inflammation, respiratory rhythmogenesis, and HIF1A-mediated hypoxic response.

Original language	English
Article number	136
Number of pages	17
Journal	Genome Medicine
Volume	13
Issue number	1
DOIs	https://doi.org/10.1186/s13073-021-00917-8
Publication status	Published - 26 Aug 2021

Keywords

Genome-wide association study
GWAS
Sleep apnea
Sleep-disordered breathing
WGS
Whole-genome sequencing

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Published versionFinal published version, 1.26 MBLicence: CC BY

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Cade, B. E., Lee, J., Sofer, T., Wang, H., Zhang, M., Chen, H., Gharib, S. A., Gottlieb, D. J., Guo, X., Lane, J. M., Liang, J., Lin, X., Mei, H., Patel, S. R., Purcell, S. M., Saxena, R., Shah, N. A., Evans, D. S., Hanis, C. L., ... TOPMed Sleep Working Group (2021). Whole-genome association analyses of sleep-disordered breathing phenotypes in the NHLBI TOPMed program. Genome Medicine, 13(1), Article 136. https://doi.org/10.1186/s13073-021-00917-8

@article{4ef3833a40e84ae1ac7563652f3f4057,

title = "Whole-genome association analyses of sleep-disordered breathing phenotypes in the NHLBI TOPMed program",

abstract = "Background: Sleep-disordered breathing is a common disorder associated with significant morbidity. The genetic architecture of sleep-disordered breathing remains poorly understood. Through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program, we performed the first whole-genome sequence analysis of sleep-disordered breathing. Methods: The study sample was comprised of 7988 individuals of diverse ancestry. Common-variant and pathway analyses included an additional 13,257 individuals. We examined five complementary traits describing different aspects of sleep-disordered breathing: the apnea-hypopnea index, average oxyhemoglobin desaturation per event, average and minimum oxyhemoglobin saturation across the sleep episode, and the percentage of sleep with oxyhemoglobin saturation < 90%. We adjusted for age, sex, BMI, study, and family structure using MMSKAT and EMMAX mixed linear model approaches. Additional bioinformatics analyses were performed with MetaXcan, GIGSEA, and ReMap. Results: We identified a multi-ethnic set-based rare-variant association (p = 3.48 × 10 −8) on chromosome X with ARMCX3. Additional rare-variant associations include ARMCX3-AS1, MRPS33, and C16orf90. Novel common-variant loci were identified in the NRG1 and SLC45A2 regions, and previously associated loci in the IL18RAP and ATP2B4 regions were associated with novel phenotypes. Transcription factor binding site enrichment identified associations with genes implicated with respiratory and craniofacial traits. Additional analyses identified significantly associated pathways. Conclusions: We have identified the first gene-based rare-variant associations with objectively measured sleep-disordered breathing traits. Our results increase the understanding of the genetic architecture of sleep-disordered breathing and highlight associations in genes that modulate lung development, inflammation, respiratory rhythmogenesis, and HIF1A-mediated hypoxic response. ",

keywords = "Genome-wide association study, GWAS, Sleep apnea, Sleep-disordered breathing, WGS, Whole-genome sequencing",

author = "Cade, {Brian E.} and Jiwon Lee and Tamar Sofer and Heming Wang and Man Zhang and Han Chen and Gharib, {Sina A.} and Gottlieb, {Daniel J.} and Xiuqing Guo and Lane, {Jacqueline M.} and Jingjing Liang and Xihong Lin and Hao Mei and Patel, {Sanjay R.} and Purcell, {Shaun M.} and Richa Saxena and Shah, {Neomi A.} and Evans, {Daniel S.} and Hanis, {Craig L.} and Hillman, {David R.} and Sutapa Mukherjee and Palmer, {Lyle J.} and Stone, {Katie L.} and Tranah, {Gregory J.} and {NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium} and Abecasis, {Gon{\c c}alo R.} and Boerwinkle, {Eric A.} and Adolfo Correa and Kaplan, {Robert C.} and Cupples, {L. Adrienne} and Nickerson, {Deborah A.} and North, {Kari E.} and Psaty, {Bruce M.} and Rotter, {Jerome I.} and Rich, {Stephen S.} and Tracy, {Russell P.} and Vasan, {Ramachandran S.} and Wilson, {James G.} and Xiaofeng Zhu and Susan Redline and {TOPMed Sleep Working Group} and Namiko Abe and Christine Albert and Laura Almasy and Alvaro Alonso and Seth Ament and Peter Anderson and Pramod Anugu and Deborah Applebaum-Bowden and Dan Arking and Arnett, {Donna K.} and Allison Ashley-Koch and Stella Aslibekyan and Tim Assimes and Paul Auer and Dimitrios Avramopoulos and John Barnard and Kathleen Barnes and Barr, {R. Graham} and Emily Barron-Casella and Terri Beaty and Diane Becker and Lewis Becker and Rebecca Beer and Ferdouse Begum and Amber Beitelshees and Emelia Benjamin and Marcos Bezerra and Larry Bielak and Joshua Bis and Thomas Blackwell and John Blangero and Borecki, {Ingrid B.} and Bowden, {Donald W.} and Russell Bowler and Jennifer Brody and Ulrich Broeckel and Jai Broome and Karen Bunting and Esteban Burchard and Jonathan Cardwell and Cara Carty and Richard Casaburi and James Casella and Mark Chaffin and Christy Chang and Daniel Chasman and Sameer Chavan and Bo-Juen Chen and Chen, {Wei Min} and Chen, {Yii Der Ida} and Michael Cho and Choi, {Seung Hoan} and Lee-Ming Chuang and Mina Chung and Elaine Cornell and Carolyn Crandall and James Crapo and Joanne Curran and Jeffrey Curtis and Brian Custer and Coleen Damcott and Dawood Darbar and Sayantan Das and Sean David and Colleen Davis and Michelle Daya and {De Andrade}, Mariza and Michael DeBaun and Ranjan Deka and Dawn DeMeo and Scott Devine and Ron Do and Qing Duan and Ravi Duggirala and Peter Durda and Susan Dutcher and Charles Eaton and Lynette Ekunwe and Patrick Ellinor and Leslie Emery and Charles Farber and Leanna Farnam and Tasha Fingerlin and Matthew Flickinger and Myriam Fornage and Nora Franceschini and Mao Fu and Fullerton, {Stephanie M.} and Lucinda Fulton and Stacey Gabriel and Weiniu Gan and Yan Gao and Margery Gass and Bruce Gelb and Geng, {Xiaoqi (Priscilla)} and Soren Germer and Chris Gignoux and Mark Gladwin and David Glahn and Stephanie Gogarten and Da-Wei Gong and Harald Goring and Gu, {C. Charles} and Yue Guan and Xiuqing Guo and Jeff Haessler and Michael Hall and Daniel Harris and Nicola Hawley and Jiang He and Ben Heavner and Susan Heckbert and Ryan Hernandez and David Herrington and Hersh, {Craig P.} and Bertha Hidalgo and James Hixson and John Hokanson and Elliott Hong and Karin Hoth and Hsiung, {Chao (Agnes)} and Haley Huston and Hwu, {Chii Min} and Irvin, {Marguerite Ryan} and Rebecca Jackson and Deepti Jain and Cashell Jaquish and Jhun, {Min A.} and Jill Johnsen and Andrew Johnson and Craig Johnson and Rich Johnston and Kimberly Jones and Kang, {Hyun Min} and Sharon Kardia and Sekar Kathiresan and Laura Kaufman and Shannon Kelly and Eimear Kenny and Michael Kessler and Greg Kinney and Barbara Konkle and Charles Kooperberg and Holly Kramer and Stephanie Krauter and Christoph Lange and Ethan Lange and Leslie Lange and Cathy Laurie and Cecelia Laurie and Meryl LeBoff and Lee, {Seunggeun Shawn} and Wen-Jane Lee and Jonathon LeFaive and David Levine and Dan Levy and Joshua Lewis and Yun Li and Honghuang Lin and Lin, {Keng Han} and Simin Liu and Yongmei Liu and Ruth Loos and Steven Lubitz and Kathryn Lunetta and James Luo and Michael Mahaney and Barry Make and Ani Manichaikul and JoAnn Manson and Lauren Margolin and Lisa Martin and Susan Mathai and Rasika Mathias and Patrick McArdle and Merry-Lynn McDonald and Sean McFarland and Stephen McGarvey and Hao Mei and Meyers, {Deborah A.} and Julie Mikulla and Nancy Min and Mollie Minear and Minster, {Ryan L.} and Mitchell, {Braxton D.} and Montasser, {May E.} and Solomon Musani and Stanford Mwasongwe and Mychaleckyj, {Josyf C.} and Girish Nadkarni and Rakhi Naik and Take Naseri and Pradeep Natarajan and Sergei Nekhai and Jeff O'Connell and Tim O'Connor and Heather Ochs-Balcom and Nicholette Palmer and James Pankow and Papanicolaou, {George J.} and Margaret Parker and Afshin Parsa and Sara Penchev and Peralta, {Juan Manuel} and Marco Perez and James Perry and Ulrike Peters and Patricia Peyser and Phillips, {Lawrence S.} and Sam Phillips and Toni Pollin",

year = "2021",

month = aug,

day = "26",

doi = "10.1186/s13073-021-00917-8",

language = "English",

volume = "13",

journal = "Genome Medicine",

issn = "1756-994X",

publisher = "BioMed Central Ltd.",

number = "1",

}

Cade, BE, Lee, J, Sofer, T, Wang, H, Zhang, M, Chen, H, Gharib, SA, Gottlieb, DJ, Guo, X, Lane, JM, Liang, J, Lin, X, Mei, H, Patel, SR, Purcell, SM, Saxena, R, Shah, NA, Evans, DS, Hanis, CL, Hillman, DR, Mukherjee, S, Palmer, LJ, Stone, KL, Tranah, GJ, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Abecasis, GR, Boerwinkle, EA, Correa, A, Kaplan, RC, Cupples, LA, Nickerson, DA, North, KE, Psaty, BM, Rotter, JI, Rich, SS, Tracy, RP, Vasan, RS, Wilson, JG, Zhu, X, Redline, S & TOPMed Sleep Working Group 2021, 'Whole-genome association analyses of sleep-disordered breathing phenotypes in the NHLBI TOPMed program', Genome Medicine, vol. 13, no. 1, 136. https://doi.org/10.1186/s13073-021-00917-8

TY - JOUR

T1 - Whole-genome association analyses of sleep-disordered breathing phenotypes in the NHLBI TOPMed program

AU - Cade, Brian E.

AU - Lee, Jiwon

AU - Sofer, Tamar

AU - Wang, Heming

AU - Zhang, Man

AU - Chen, Han

AU - Gharib, Sina A.

AU - Gottlieb, Daniel J.

AU - Guo, Xiuqing

AU - Lane, Jacqueline M.

AU - Liang, Jingjing

AU - Lin, Xihong

AU - Mei, Hao

AU - Patel, Sanjay R.

AU - Purcell, Shaun M.

AU - Saxena, Richa

AU - Shah, Neomi A.

AU - Evans, Daniel S.

AU - Hanis, Craig L.

AU - Hillman, David R.

AU - Mukherjee, Sutapa

AU - Palmer, Lyle J.

AU - Stone, Katie L.

AU - Tranah, Gregory J.

AU - NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium

AU - Abecasis, Gonçalo R.

AU - Boerwinkle, Eric A.

AU - Correa, Adolfo

AU - Kaplan, Robert C.

AU - Cupples, L. Adrienne

AU - Nickerson, Deborah A.

AU - North, Kari E.

AU - Psaty, Bruce M.

AU - Rotter, Jerome I.

AU - Rich, Stephen S.

AU - Tracy, Russell P.

AU - Vasan, Ramachandran S.

AU - Wilson, James G.

AU - Zhu, Xiaofeng

AU - Redline, Susan

AU - TOPMed Sleep Working Group

AU - Abe, Namiko

AU - Albert, Christine

AU - Almasy, Laura

AU - Alonso, Alvaro

AU - Ament, Seth

AU - Anderson, Peter

AU - Anugu, Pramod

AU - Applebaum-Bowden, Deborah

AU - Arking, Dan

AU - Arnett, Donna K.

AU - Ashley-Koch, Allison

AU - Aslibekyan, Stella

AU - Assimes, Tim

AU - Auer, Paul

AU - Avramopoulos, Dimitrios

AU - Barnard, John

AU - Barnes, Kathleen

AU - Barr, R. Graham

AU - Barron-Casella, Emily

AU - Beaty, Terri

AU - Becker, Diane

AU - Becker, Lewis

AU - Beer, Rebecca

AU - Begum, Ferdouse

AU - Beitelshees, Amber

AU - Benjamin, Emelia

AU - Bezerra, Marcos

AU - Bielak, Larry

AU - Bis, Joshua

AU - Blackwell, Thomas

AU - Blangero, John

AU - Borecki, Ingrid B.

AU - Bowden, Donald W.

AU - Bowler, Russell

AU - Brody, Jennifer

AU - Broeckel, Ulrich

AU - Broome, Jai

AU - Bunting, Karen

AU - Burchard, Esteban

AU - Cardwell, Jonathan

AU - Carty, Cara

AU - Casaburi, Richard

AU - Casella, James

AU - Chaffin, Mark

AU - Chang, Christy

AU - Chasman, Daniel

AU - Chavan, Sameer

AU - Chen, Bo-Juen

AU - Chen, Wei Min

AU - Chen, Yii Der Ida

AU - Cho, Michael

AU - Choi, Seung Hoan

AU - Chuang, Lee-Ming

AU - Chung, Mina

AU - Cornell, Elaine

AU - Crandall, Carolyn

AU - Crapo, James

AU - Curran, Joanne

AU - Curtis, Jeffrey

AU - Custer, Brian

AU - Damcott, Coleen

AU - Darbar, Dawood

AU - Das, Sayantan

AU - David, Sean

AU - Davis, Colleen

AU - Daya, Michelle

AU - De Andrade, Mariza

AU - DeBaun, Michael

AU - Deka, Ranjan

AU - DeMeo, Dawn

AU - Devine, Scott

AU - Do, Ron

AU - Duan, Qing

AU - Duggirala, Ravi

AU - Durda, Peter

AU - Dutcher, Susan

AU - Eaton, Charles

AU - Ekunwe, Lynette

AU - Ellinor, Patrick

AU - Emery, Leslie

AU - Farber, Charles

AU - Farnam, Leanna

AU - Fingerlin, Tasha

AU - Flickinger, Matthew

AU - Fornage, Myriam

AU - Franceschini, Nora

AU - Fu, Mao

AU - Fullerton, Stephanie M.

AU - Fulton, Lucinda

AU - Gabriel, Stacey

AU - Gan, Weiniu

AU - Gao, Yan

AU - Gass, Margery

AU - Gelb, Bruce

AU - Geng, Xiaoqi (Priscilla)

AU - Germer, Soren

AU - Gignoux, Chris

AU - Gladwin, Mark

AU - Glahn, David

AU - Gogarten, Stephanie

AU - Gong, Da-Wei

AU - Goring, Harald

AU - Gu, C. Charles

AU - Guan, Yue

AU - Guo, Xiuqing

AU - Haessler, Jeff

AU - Hall, Michael

AU - Harris, Daniel

AU - Hawley, Nicola

AU - He, Jiang

AU - Heavner, Ben

AU - Heckbert, Susan

AU - Hernandez, Ryan

AU - Herrington, David

AU - Hersh, Craig P.

AU - Hidalgo, Bertha

AU - Hixson, James

AU - Hokanson, John

AU - Hong, Elliott

AU - Hoth, Karin

AU - Hsiung, Chao (Agnes)

AU - Huston, Haley

AU - Hwu, Chii Min

AU - Irvin, Marguerite Ryan

AU - Jackson, Rebecca

AU - Jain, Deepti

AU - Jaquish, Cashell

AU - Jhun, Min A.

AU - Johnsen, Jill

AU - Johnson, Andrew

AU - Johnson, Craig

AU - Johnston, Rich

AU - Jones, Kimberly

AU - Kang, Hyun Min

AU - Kardia, Sharon

AU - Kathiresan, Sekar

AU - Kaufman, Laura

AU - Kelly, Shannon

AU - Kenny, Eimear

AU - Kessler, Michael

AU - Kinney, Greg

AU - Konkle, Barbara

AU - Kooperberg, Charles

AU - Kramer, Holly

AU - Krauter, Stephanie

AU - Lange, Christoph

AU - Lange, Ethan

AU - Lange, Leslie

AU - Laurie, Cathy

AU - Laurie, Cecelia

AU - LeBoff, Meryl

AU - Lee, Seunggeun Shawn

AU - Lee, Wen-Jane

AU - LeFaive, Jonathon

AU - Levine, David

AU - Levy, Dan

AU - Lewis, Joshua

AU - Li, Yun

AU - Lin, Honghuang

AU - Lin, Keng Han

AU - Liu, Simin

AU - Liu, Yongmei

AU - Loos, Ruth

AU - Lubitz, Steven

AU - Lunetta, Kathryn

AU - Luo, James

AU - Mahaney, Michael

AU - Make, Barry

AU - Manichaikul, Ani

AU - Manson, JoAnn

AU - Margolin, Lauren

AU - Martin, Lisa

AU - Mathai, Susan

AU - Mathias, Rasika

AU - McArdle, Patrick

AU - McDonald, Merry-Lynn

AU - McFarland, Sean

AU - McGarvey, Stephen

AU - Mei, Hao

AU - Meyers, Deborah A.

AU - Mikulla, Julie

AU - Min, Nancy

AU - Minear, Mollie

AU - Minster, Ryan L.

AU - Mitchell, Braxton D.

AU - Montasser, May E.

AU - Musani, Solomon

AU - Mwasongwe, Stanford

AU - Mychaleckyj, Josyf C.

AU - Nadkarni, Girish

AU - Naik, Rakhi

AU - Naseri, Take

AU - Natarajan, Pradeep

AU - Nekhai, Sergei

AU - O'Connell, Jeff

AU - O'Connor, Tim

AU - Ochs-Balcom, Heather

AU - Palmer, Nicholette

AU - Pankow, James

AU - Papanicolaou, George J.

AU - Parker, Margaret

AU - Parsa, Afshin

AU - Penchev, Sara

AU - Peralta, Juan Manuel

AU - Perez, Marco

AU - Perry, James

AU - Peters, Ulrike

AU - Peyser, Patricia

AU - Phillips, Lawrence S.

AU - Phillips, Sam

AU - Pollin, Toni

PY - 2021/8/26

Y1 - 2021/8/26

N2 - Background: Sleep-disordered breathing is a common disorder associated with significant morbidity. The genetic architecture of sleep-disordered breathing remains poorly understood. Through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program, we performed the first whole-genome sequence analysis of sleep-disordered breathing. Methods: The study sample was comprised of 7988 individuals of diverse ancestry. Common-variant and pathway analyses included an additional 13,257 individuals. We examined five complementary traits describing different aspects of sleep-disordered breathing: the apnea-hypopnea index, average oxyhemoglobin desaturation per event, average and minimum oxyhemoglobin saturation across the sleep episode, and the percentage of sleep with oxyhemoglobin saturation < 90%. We adjusted for age, sex, BMI, study, and family structure using MMSKAT and EMMAX mixed linear model approaches. Additional bioinformatics analyses were performed with MetaXcan, GIGSEA, and ReMap. Results: We identified a multi-ethnic set-based rare-variant association (p = 3.48 × 10 −8) on chromosome X with ARMCX3. Additional rare-variant associations include ARMCX3-AS1, MRPS33, and C16orf90. Novel common-variant loci were identified in the NRG1 and SLC45A2 regions, and previously associated loci in the IL18RAP and ATP2B4 regions were associated with novel phenotypes. Transcription factor binding site enrichment identified associations with genes implicated with respiratory and craniofacial traits. Additional analyses identified significantly associated pathways. Conclusions: We have identified the first gene-based rare-variant associations with objectively measured sleep-disordered breathing traits. Our results increase the understanding of the genetic architecture of sleep-disordered breathing and highlight associations in genes that modulate lung development, inflammation, respiratory rhythmogenesis, and HIF1A-mediated hypoxic response.

AB - Background: Sleep-disordered breathing is a common disorder associated with significant morbidity. The genetic architecture of sleep-disordered breathing remains poorly understood. Through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program, we performed the first whole-genome sequence analysis of sleep-disordered breathing. Methods: The study sample was comprised of 7988 individuals of diverse ancestry. Common-variant and pathway analyses included an additional 13,257 individuals. We examined five complementary traits describing different aspects of sleep-disordered breathing: the apnea-hypopnea index, average oxyhemoglobin desaturation per event, average and minimum oxyhemoglobin saturation across the sleep episode, and the percentage of sleep with oxyhemoglobin saturation < 90%. We adjusted for age, sex, BMI, study, and family structure using MMSKAT and EMMAX mixed linear model approaches. Additional bioinformatics analyses were performed with MetaXcan, GIGSEA, and ReMap. Results: We identified a multi-ethnic set-based rare-variant association (p = 3.48 × 10 −8) on chromosome X with ARMCX3. Additional rare-variant associations include ARMCX3-AS1, MRPS33, and C16orf90. Novel common-variant loci were identified in the NRG1 and SLC45A2 regions, and previously associated loci in the IL18RAP and ATP2B4 regions were associated with novel phenotypes. Transcription factor binding site enrichment identified associations with genes implicated with respiratory and craniofacial traits. Additional analyses identified significantly associated pathways. Conclusions: We have identified the first gene-based rare-variant associations with objectively measured sleep-disordered breathing traits. Our results increase the understanding of the genetic architecture of sleep-disordered breathing and highlight associations in genes that modulate lung development, inflammation, respiratory rhythmogenesis, and HIF1A-mediated hypoxic response.

KW - Genome-wide association study

KW - GWAS

KW - Sleep apnea

KW - Sleep-disordered breathing

KW - WGS

KW - Whole-genome sequencing

UR - http://www.scopus.com/inward/record.url?scp=85115041107&partnerID=8YFLogxK

U2 - 10.1186/s13073-021-00917-8

DO - 10.1186/s13073-021-00917-8

M3 - Article

C2 - 34446064

AN - SCOPUS:85115041107

SN - 1756-994X

VL - 13

JO - Genome Medicine

JF - Genome Medicine

IS - 1

M1 - 136

ER -

Whole-genome association analyses of sleep-disordered breathing phenotypes in the NHLBI TOPMed program

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Keywords

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