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

TOPMed Sleep Working Group; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium

doi:10.1186/s13073-021-00917-8

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

TOPMed Sleep Working Group, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium

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

10 Scopus citations

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
Journal	Genome medicine
Volume	13
Issue number	1
DOIs	https://doi.org/10.1186/s13073-021-00917-8
State	Published - Dec 2021

Keywords

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

Access to Document

10.1186/s13073-021-00917-8

Cite this

@article{c2cff1348e3b413697a3b0bb5e2a416f,

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

author = "{TOPMed Sleep Working Group} and {NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium} and 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 Abecasis, {Gon{\c c}alo R.} and Goncalo Abecasis and Boerwinkle, {Eric A.} and Laura Almasy and Alvaro Alonso and Seth Ament and Peter Anderson and Pramod Anugu and Rotter, {Jerome I.} and Dan Arking and Arnett, {Donna K.} and Allison Ashley-Koch and Stella Aslibekyan and Xiaofeng Zhu and Susan Redline 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 Eric Boerwinkle and Ingrid Borecki and Bowden, {Donald W.} and Russell Bowler and Jennifer Brody and Ulrich Broeckel and Jai Broome and Karen Bunting and Esteban Burchard and Brian Cade 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 Chen, {Bo Juen} and Chen, {Wei Min} and Chen, {Yii Der Ida} and Michael Cho and Choi, {Seung Hoan} and Chuang, {Lee Ming} 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 Gong, {Da Wei} and Harald Goring and Gu, {C. Charles} and Yue Guan 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 Craig Hersh 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 Robert Kaplan and Sharon Kardia and Sekar Kathiresan and Laura Kaufman and Shannon Kelly and Eimear Kenny and Michael Kessler and Alyna Khan 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 Lee, {Wen Jane} 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 Manson, {Jo Ann} and Rao, {D. C.} and Sung, {Yun Ju}",

note = "Funding Information: Whole-genome sequencing (WGS) for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung, and Blood Institute (NHLBI). WGS for “NHLBI TOPMed: Trans-Omics for Precision Medicine Whole Genome Sequencing Project: ARIC” (phs001211.v1.p1) was performed at Baylor College of Medicine Human Genome Sequencing Center (HHSN268201500015C and 3U54HG003273-12S2) and the Broad Institute of MIT and Harvard (3R01HL092577-06S1). WGS for “NHLBI TOPMed: The Cleveland Family Study (WGS)” (phs000954.v2.p1) was performed at the University of Washington Northwest Genomics Center (3R01HL098433-05S1). WGS for “NHLBI TOPMed: Cardiovascular Health Study” (phs001368.v1.p1) was performed at Baylor College of Medicine Human Genome Sequencing Center (HHSN268201500015C). WGS for “NHLBI TOPMed: Whole Genome Sequencing and Related Phenotypes in the Framingham Heart Study” (phs000974.v3.p2) was performed at the Broad Institute of MIT and Harvard (3R01HL092577-06S1). WGS for “NHLBI TOPMed: Hispanic Community Health Study/Study of Latinos (HCHS/SOL)” (phs001395) was performed at the Baylor College of Medicine Human Genome Sequencing Center (HHSN268201500015C and 3U54HG003273-12S2). WGS for “NHLBI TOPMed: The Jackson Heart Study” (phs000964.v3.p1) was performed at the University of Washington Northwest Genomics Center (HHSN268201100037C). WGS for “NHLBI TOPMed: NHLBI TOPMed: MESA” (phs001416.v1.p1) was performed at the Broad Institute of MIT and Harvard (3U54HG003067-13S1). Centralized read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1). Phenotype harmonization, data management, sample-identity QC, and general study coordination were provided by the TOPMed Data Coordinating Center (3R01HL-120393-02S1). Funding Information: The Genome Sequencing Program (GSP) was funded by the National Human Genome Research Institute (NHGRI); the National Heart, Lung, and Blood Institute (NHLBI); and the National Eye Institute (NEI). The GSP Coordinating Center (U24 HG008956) contributed to cross-program scientific initiatives and provided logistical and general study coordination. The Centers for Common Disease Genomics (CCDG) program was supported by NHGRI and NHLBI, and CCDG-funded whole-genome sequencing of the ARIC and HCHS/SOL studies was performed at the Baylor College of Medicine Human Genome Sequencing Center (UM1 HG008898 and R01HL059367). Funding Information: The Starr County Health Studies is supported in part by grants R01 DK073541, U01 DK085501, R01 AI085014, and R01 HL102830 from the National Institutes of Health, and funds from the University of Texas Health Science Center at Houston. Funding Information: We acknowledge our TOPMed Consortium and TOPMed Sleep Traits Working Group collaborators, who are listed in Additional file 1 : Tables S1 and S2. The authors wish to thank the participants and study staff of all of our cohorts for their important contributions. We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. The authors thank the staff and participants of the ARIC study for their important contributions. A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The Framingham Heart Study thanks the study participants and the multitude of investigators who over its 70-year history continue to contribute so much to further our knowledge of heart, lung, blood, and sleep disorders and associated traits. The authors thank the staff and participants of HCHS/SOL for their important contributions. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the US Department of Health and Human Services. This manuscript was not approved by the HCHS/SOL publications committee. Investigator?s website?http://www.cscc.unc.edu/hchs/. The authors also wish to thank the staff and participants of the JHS. We thank the field staff in Starr County for their careful collection of these data and are especially grateful to the participants who so graciously cooperated and gave of their time. Funding Information: Brian Cade is supported by grants from the National Institutes of Health [K01-HL135405-01, R01-HL113338-04, R35-HL135818-01] and the American Thoracic Society Foundation ( http://foundation.thoracic.org ). Susan Redline is partially supported by grants from the National Institutes of Health [R35-HL135818-01, R01-HL113338-04]. Sanjay Patel has had grant support through his institution from the ResMed Foundation, the American Sleep Medicine Foundation, Bayer Pharmaceuticals, and Philips Respironics. James Wilson is supported by U54GM115428 from the National Institute of General Medical Sciences. Funding Information: The Cleveland Family Study has been supported by National Institutes of Health grants [R01-HL046380, KL2-RR024990, R35-HL135818, and R01-HL113338]. Funding Information: The Atherosclerosis Risk in Communities (ARIC) study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I, and HHSN268201700005I), R01HL087641, R01HL059367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. Funding Information: This Cardiovascular Health Study (CHS) research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, HHSN268200960009C, HHSN268201800001C N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and N01HC85086 and NHLBI grants U01HL080295, U01HL130114, R01HL087652, R01HL105756, R01HL103612, R01HL085251, and R01HL120393 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA). Funding Information: The Hispanic Community Health Study/Study of Latinos was carried out as a collaborative study supported by contracts from the NHLBI to the University of North Carolina (HHSN268201300001I/N01-HC65233), University of Miami (HHSN268201300004I/N01-HC65234), Albert Einstein College of Medicine (HHSN268201300002I/N01-HC65235), University of Illinois at Chicago (HHSN268201300003I), Northwestern University (N01-HC65236), and San Diego State University (HHSN268201300005I/N01-HC65237). The following Institutes/Centers/Offices contribute to the HCHS/SOL through a transfer of funds to the NHLBI: National Institute on Minority Health and Health Disparities, National Institute on Deafness and Other Communication Disorders, National Institute of Dental and Craniofacial Research, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, and NIH Institution-Office of Dietary Supplements. The Genetic Analysis Center at Washington University was supported by NHLBI and NIDCR contracts (HHSN268201300005C AM03 and MOD03). Funding Information: The Jackson Heart Study (JHS) is supported and conducted in collaboration with Jackson State University (HHSN268201800013I), Tougaloo College (HHSN268201800014I), the Mississippi State Department of Health (HHSN268201800015I/HHSN26800001) and the University of Mississippi Medical Center (HHSN268201800010I, HHSN268201800011I, and HHSN268201800012I) contracts from the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute for Minority Health and Health Disparities (NIMHD). Funding Information: Funding for the Western Australian Sleep Health Study was obtained from the Sir Charles Gairdner and Hollywood Private Hospital Research Foundations, the Western Australian Sleep Disorders Research Institute, and the Centre for Genetic Epidemiology and Biostatistics at the University of Western Australia. Funding for the GWAS genotyping was obtained from the Ontario Institute for Cancer Research and a McLaughlin Centre Accelerator Grant from the University of Toronto. Funding Information: MESA and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420. Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-64278. Genotyping was performed at Affymetrix (Santa Clara, California, USA) and the Broad Institute of Harvard and MIT (Boston, Massachusetts, USA) using the Affymetrix Genome-Wide Human SNP Array 6.0. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. Funding Information: The Osteoporotic Fractures in Men (MrOS) Study is supported by NIH funding. The following institutes provide support: the National Institute on Aging (NIA), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NCATS, and NIH Roadmap for Medical Research under the following grant numbers: U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160, and UL1 TR000128. The NHLBI provides funding for the MrOS Sleep ancillary study “Outcomes of Sleep Disorders in Older Men” under the following grant numbers: R01 HL071194, R01 HL070848, R01 HL070847, R01 HL070842, R01 HL070841, R01 HL070837, R01 HL070838, and R01 HL070839. The NIAMS provides funding for the MrOS ancillary study “Replication of candidate gene associations and bone strength phenotype in MrOS” under the grant number R01 AR051124. The NIAMS provides funding for the MrOS ancillary study “GWAS in MrOS and SOF” under the grant number RC2 AR058973. Funding Information: The authors disclose the following industry funding, which they believe is unrelated to this study. SRP has had grant support through his institution from the ResMed Foundation, Bayer Pharmaceuticals, and Philips Respironics. BMP serves on the Steering Committee of the Yale Open Data Access Project, funded by Johnson & Johnson. KLS has grant funding from Merck. The remaining authors declare that they have no competing interests. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

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

language = "English",

volume = "13",

journal = "Genome medicine",

issn = "1756-994X",

number = "1",

}

TY - JOUR

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

AU - TOPMed Sleep Working Group

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

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 - Abecasis, Gonçalo R.

AU - Abecasis, Goncalo

AU - Boerwinkle, Eric A.

AU - Almasy, Laura

AU - Alonso, Alvaro

AU - Ament, Seth

AU - Anderson, Peter

AU - Anugu, Pramod

AU - Rotter, Jerome I.

AU - Arking, Dan

AU - Arnett, Donna K.

AU - Ashley-Koch, Allison

AU - Aslibekyan, Stella

AU - Zhu, Xiaofeng

AU - Redline, Susan

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 - Boerwinkle, Eric

AU - Borecki, Ingrid

AU - Bowden, Donald W.

AU - Bowler, Russell

AU - Brody, Jennifer

AU - Broeckel, Ulrich

AU - Broome, Jai

AU - Bunting, Karen

AU - Burchard, Esteban

AU - Cade, Brian

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 - 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

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 - Kaplan, Robert

AU - Kardia, Sharon

AU - Kathiresan, Sekar

AU - Kaufman, Laura

AU - Kelly, Shannon

AU - Kenny, Eimear

AU - Kessler, Michael

AU - Khan, Alyna

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, Jo Ann

AU - Rao, D. C.

AU - Sung, Yun Ju

N1 - Funding Information: Whole-genome sequencing (WGS) for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung, and Blood Institute (NHLBI). WGS for “NHLBI TOPMed: Trans-Omics for Precision Medicine Whole Genome Sequencing Project: ARIC” (phs001211.v1.p1) was performed at Baylor College of Medicine Human Genome Sequencing Center (HHSN268201500015C and 3U54HG003273-12S2) and the Broad Institute of MIT and Harvard (3R01HL092577-06S1). WGS for “NHLBI TOPMed: The Cleveland Family Study (WGS)” (phs000954.v2.p1) was performed at the University of Washington Northwest Genomics Center (3R01HL098433-05S1). WGS for “NHLBI TOPMed: Cardiovascular Health Study” (phs001368.v1.p1) was performed at Baylor College of Medicine Human Genome Sequencing Center (HHSN268201500015C). WGS for “NHLBI TOPMed: Whole Genome Sequencing and Related Phenotypes in the Framingham Heart Study” (phs000974.v3.p2) was performed at the Broad Institute of MIT and Harvard (3R01HL092577-06S1). WGS for “NHLBI TOPMed: Hispanic Community Health Study/Study of Latinos (HCHS/SOL)” (phs001395) was performed at the Baylor College of Medicine Human Genome Sequencing Center (HHSN268201500015C and 3U54HG003273-12S2). WGS for “NHLBI TOPMed: The Jackson Heart Study” (phs000964.v3.p1) was performed at the University of Washington Northwest Genomics Center (HHSN268201100037C). WGS for “NHLBI TOPMed: NHLBI TOPMed: MESA” (phs001416.v1.p1) was performed at the Broad Institute of MIT and Harvard (3U54HG003067-13S1). Centralized read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1). Phenotype harmonization, data management, sample-identity QC, and general study coordination were provided by the TOPMed Data Coordinating Center (3R01HL-120393-02S1). Funding Information: The Genome Sequencing Program (GSP) was funded by the National Human Genome Research Institute (NHGRI); the National Heart, Lung, and Blood Institute (NHLBI); and the National Eye Institute (NEI). The GSP Coordinating Center (U24 HG008956) contributed to cross-program scientific initiatives and provided logistical and general study coordination. The Centers for Common Disease Genomics (CCDG) program was supported by NHGRI and NHLBI, and CCDG-funded whole-genome sequencing of the ARIC and HCHS/SOL studies was performed at the Baylor College of Medicine Human Genome Sequencing Center (UM1 HG008898 and R01HL059367). Funding Information: The Starr County Health Studies is supported in part by grants R01 DK073541, U01 DK085501, R01 AI085014, and R01 HL102830 from the National Institutes of Health, and funds from the University of Texas Health Science Center at Houston. Funding Information: We acknowledge our TOPMed Consortium and TOPMed Sleep Traits Working Group collaborators, who are listed in Additional file 1 : Tables S1 and S2. The authors wish to thank the participants and study staff of all of our cohorts for their important contributions. We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. The authors thank the staff and participants of the ARIC study for their important contributions. A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The Framingham Heart Study thanks the study participants and the multitude of investigators who over its 70-year history continue to contribute so much to further our knowledge of heart, lung, blood, and sleep disorders and associated traits. The authors thank the staff and participants of HCHS/SOL for their important contributions. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the US Department of Health and Human Services. This manuscript was not approved by the HCHS/SOL publications committee. Investigator?s website?http://www.cscc.unc.edu/hchs/. The authors also wish to thank the staff and participants of the JHS. We thank the field staff in Starr County for their careful collection of these data and are especially grateful to the participants who so graciously cooperated and gave of their time. Funding Information: Brian Cade is supported by grants from the National Institutes of Health [K01-HL135405-01, R01-HL113338-04, R35-HL135818-01] and the American Thoracic Society Foundation ( http://foundation.thoracic.org ). Susan Redline is partially supported by grants from the National Institutes of Health [R35-HL135818-01, R01-HL113338-04]. Sanjay Patel has had grant support through his institution from the ResMed Foundation, the American Sleep Medicine Foundation, Bayer Pharmaceuticals, and Philips Respironics. James Wilson is supported by U54GM115428 from the National Institute of General Medical Sciences. Funding Information: The Cleveland Family Study has been supported by National Institutes of Health grants [R01-HL046380, KL2-RR024990, R35-HL135818, and R01-HL113338]. Funding Information: The Atherosclerosis Risk in Communities (ARIC) study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I, and HHSN268201700005I), R01HL087641, R01HL059367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. Funding Information: This Cardiovascular Health Study (CHS) research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, HHSN268200960009C, HHSN268201800001C N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and N01HC85086 and NHLBI grants U01HL080295, U01HL130114, R01HL087652, R01HL105756, R01HL103612, R01HL085251, and R01HL120393 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA). Funding Information: The Hispanic Community Health Study/Study of Latinos was carried out as a collaborative study supported by contracts from the NHLBI to the University of North Carolina (HHSN268201300001I/N01-HC65233), University of Miami (HHSN268201300004I/N01-HC65234), Albert Einstein College of Medicine (HHSN268201300002I/N01-HC65235), University of Illinois at Chicago (HHSN268201300003I), Northwestern University (N01-HC65236), and San Diego State University (HHSN268201300005I/N01-HC65237). The following Institutes/Centers/Offices contribute to the HCHS/SOL through a transfer of funds to the NHLBI: National Institute on Minority Health and Health Disparities, National Institute on Deafness and Other Communication Disorders, National Institute of Dental and Craniofacial Research, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, and NIH Institution-Office of Dietary Supplements. The Genetic Analysis Center at Washington University was supported by NHLBI and NIDCR contracts (HHSN268201300005C AM03 and MOD03). Funding Information: The Jackson Heart Study (JHS) is supported and conducted in collaboration with Jackson State University (HHSN268201800013I), Tougaloo College (HHSN268201800014I), the Mississippi State Department of Health (HHSN268201800015I/HHSN26800001) and the University of Mississippi Medical Center (HHSN268201800010I, HHSN268201800011I, and HHSN268201800012I) contracts from the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute for Minority Health and Health Disparities (NIMHD). Funding Information: Funding for the Western Australian Sleep Health Study was obtained from the Sir Charles Gairdner and Hollywood Private Hospital Research Foundations, the Western Australian Sleep Disorders Research Institute, and the Centre for Genetic Epidemiology and Biostatistics at the University of Western Australia. Funding for the GWAS genotyping was obtained from the Ontario Institute for Cancer Research and a McLaughlin Centre Accelerator Grant from the University of Toronto. Funding Information: MESA and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420. Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-64278. Genotyping was performed at Affymetrix (Santa Clara, California, USA) and the Broad Institute of Harvard and MIT (Boston, Massachusetts, USA) using the Affymetrix Genome-Wide Human SNP Array 6.0. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. Funding Information: The Osteoporotic Fractures in Men (MrOS) Study is supported by NIH funding. The following institutes provide support: the National Institute on Aging (NIA), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NCATS, and NIH Roadmap for Medical Research under the following grant numbers: U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160, and UL1 TR000128. The NHLBI provides funding for the MrOS Sleep ancillary study “Outcomes of Sleep Disorders in Older Men” under the following grant numbers: R01 HL071194, R01 HL070848, R01 HL070847, R01 HL070842, R01 HL070841, R01 HL070837, R01 HL070838, and R01 HL070839. The NIAMS provides funding for the MrOS ancillary study “Replication of candidate gene associations and bone strength phenotype in MrOS” under the grant number R01 AR051124. The NIAMS provides funding for the MrOS ancillary study “GWAS in MrOS and SOF” under the grant number RC2 AR058973. Funding Information: The authors disclose the following industry funding, which they believe is unrelated to this study. SRP has had grant support through his institution from the ResMed Foundation, Bayer Pharmaceuticals, and Philips Respironics. BMP serves on the Steering Committee of the Yale Open Data Access Project, funded by Johnson & Johnson. KLS has grant funding from Merck. The remaining authors declare that they have no competing interests. Publisher Copyright: © 2021, The Author(s).

PY - 2021/12

Y1 - 2021/12

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 - GWAS

KW - Genome-wide association study

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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