Whole-genome association analyses of sleep-disordered breathing phenotypes in the NHLBI TOPMed program
Authors: Cade Brian E. , Lee Jiwon , Sofer Tamar , Wang Heming , Zhang Man , Chen Han , Gharib Sina A. , Gottlieb Daniel J. , Guo Xiuqing , Lane Jacqueline M. , Liang Jingjing , Lin Xihong , Mei Hao , Patel Sanjay R. , Purcell Shaun M. , Saxena Richa , Shah Neomi A. , Evans Daniel S. , Hanis Craig L. , Hillman David R. , Mukherjee Sutapa , Palmer Lyle J. , Stone Katie L. , Tranah Gregory J. ,   NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Abe Namiko , Abecasis Goncalo , Albert Christine , Almasy Laura , Alonso Alvaro , Ament Seth , Anderson Peter , Anugu Pramod , Applebaum-Bowden Deborah , Arking Dan , Arnett Donna K. , Ashley-Koch Allison , Aslibekyan Stella , Assimes Tim , Auer Paul , Avramopoulos Dimitrios , Barnard John , Barnes Kathleen , Barr R. Graham , Barron-Casella Emily , Beaty Terri , Becker Diane , Becker Lewis , Beer Rebecca , Begum Ferdouse , Beitelshees Amber , Benjamin Emelia , Bezerra Marcos , Bielak Larry , Bis Joshua , Blackwell Thomas , Blangero John , Boerwinkle Eric , Borecki Ingrid , Bowden Donald W. , Bowler Russell , Brody Jennifer , Broeckel Ulrich , Broome Jai , Bunting Karen , Burchard Esteban , Cade Brian , Cardwell Jonathan , Carty Cara , Casaburi Richard , Casella James , Chaffin Mark , Chang Christy , Chasman Daniel , Chavan Sameer , Chen Bo-Juen , Chen Wei-Min , Chen Yii-Der Ida , Cho Michael , Choi Seung Hoan , Chuang Lee-Ming , Chung Mina , Cornell Elaine , Correa Adolfo , Crandall Carolyn , Crapo James , Cupples L. Adrienne , Curran Joanne , Curtis Jeffrey , Custer Brian , Damcott Coleen , Darbar Dawood , Das Sayantan , David Sean , Davis Colleen , Daya Michelle , de Andrade Mariza , DeBaun Michael , Deka Ranjan , DeMeo Dawn , Devine Scott , Do Ron , Duan Qing , Duggirala Ravi , Durda Peter , Dutcher Susan , Eaton Charles , Ekunwe Lynette , Ellinor Patrick , Emery Leslie , Farber Charles , Farnam Leanna , Fingerlin Tasha , Flickinger Matthew , Fornage Myriam , Franceschini Nora , Fu Mao , Fullerton Stephanie M. , Fulton Lucinda , Gabriel Stacey , Gan Weiniu , Gao Yan , Gass Margery , Gelb Bruce , Geng Xiaoqi Priscilla , Germer Soren , Gignoux Chris , Gladwin Mark , Glahn David , Gogarten Stephanie , Gong Da-Wei , Goring Harald , Gu C. Charles , Guan Yue , Guo Xiuqing , Haessler Jeff , Hall Michael , Harris Daniel , Hawley Nicola , He Jiang , Heavner Ben , Heckbert Susan , Hernandez Ryan , Herrington David , Hersh Craig , Hidalgo Bertha , Hixson James , Hokanson John , Hong Elliott , Hoth Karin , Hsiung Chao Agnes , Huston Haley , Hwu Chii Min , Irvin Marguerite Ryan , Jackson Rebecca , Jain Deepti , Jaquish Cashell , Jhun Min A. , Johnsen Jill , Johnson Andrew , Johnson Craig , Johnston Rich , Jones Kimberly , Kang Hyun Min , Kaplan Robert , Kardia Sharon , Kathiresan Sekar , Kaufman Laura , Kelly Shannon , Kenny Eimear , Kessler Michael , Khan Alyna , Kinney Greg , Konkle Barbara , Kooperberg Charles , Kramer Holly , Krauter Stephanie , Lange Christoph , Lange Ethan , Lange Leslie , Laurie Cathy , Laurie Cecelia , LeBoff Meryl , Lee Jiwon , Lee Seunggeun Shawn , Lee Wen-Jane , LeFaive Jonathon , Levine David , Levy Dan , Lewis Joshua , Li Yun , Lin Honghuang , Lin Keng Han , Lin Xihong , Liu Simin , Liu Yongmei , Loos Ruth , Lubitz Steven , Lunetta Kathryn , Luo James , Mahaney Michael , Make Barry , Manichaikul Ani , Manson Jo Ann , Margolin Lauren , Martin Lisa , Mathai Susan , Mathias Rasika , McArdle Patrick , McDonald Merry-Lynn , McFarland Sean , McGarvey Stephen , Mei Hao , Meyers Deborah A. , Mikulla Julie , Min Nancy , Minear Mollie , Minster Ryan L. , Mitchell Braxton D. , Montasser May E. , Musani Solomon , Mwasongwe Stanford , Mychaleckyj Josyf C. , Nadkarni Girish , Naik Rakhi , Naseri Take , Natarajan Pradeep , Nekhai Sergei , Nickerson Deborah , North Kari , O’Connell Jeff , O’Connor Tim , Ochs-Balcom Heather , Palmer Nicholette , Pankow James , Papanicolaou George , Parker Margaret , Parsa Afshin , Penchev Sara , Peralta Juan Manuel , Perez Marco , Perry James , Peters Ulrike , Peyser Patricia , Phillips Lawrence S. , Phillips Sam , Pollin Toni , Post Wendy , Powers Becker Julia , Preethi Boorgula Meher , Preuss Michael , Prokopenko Dmitry , Psaty Bruce , Qasba Pankaj , Qiao Dandi , Qin Zhaohui , Rafaels Nicholas , Raffield Laura , Rao D. C. , Rasmussen-Torvik Laura , Ratan Aakrosh , Redline Susan , Reed Robert , Regan Elizabeth , Reiner Alex , Reupena Muagututi‘a Sefuiva , Rice Ken , Rich Stephen , Roden Dan , Roselli Carolina , Rotter Jerome , Ruczinski Ingo , Russell Pamela , Ruuska Sarah , Ryan Kathleen , Sakornsakolpat Phuwanat , Salimi Shabnam , Salzberg Steven , Sandow Kevin , Sankaran Vijay , Scheller Christopher , Schmidt Ellen , Schwander Karen , Schwartz David , Sciurba Frank , Seidman Christine , Seidman Jonathan , Sheehan Vivien , Shetty Amol , Shetty Aniket , Sheu Wayne Hui-Heng , Shoemaker M. Benjamin , Silver Brian , Silverman Edwin , Smith Jennifer , Smith Josh , Smith Nicholas , Smith Tanja , Smoller Sylvia , Snively Beverly , Sofer Tamar , Sotoodehnia Nona , Stilp Adrienne , Streeten Elizabeth , Su Jessica Lasky , Sung Yun Ju , Sylvia Jody , Szpiro Adam , Sztalryd Carole , Taliun Daniel , Tang Hua , Taub Margaret , Taylor Kent D. , Taylor Simeon , Telen Marilyn , Thornton Timothy A. , Tinker Lesley , Tirschwell David , Tiwari Hemant , Tracy Russell , Tsai Michael , Vaidya Dhananjay , VandeHaar Peter , Vasan Ramachandran S. , Vrieze Scott , Walker Tarik , Wallace Robert , Walts Avram , Wan Emily , Wang Fei Fei , Wang Heming , Watson Karol , Weeks Daniel E. , Weir Bruce , Weiss Scott , Weng Lu-Chen , Willer Cristen , Williams Kayleen , Williams L. Keoki , Wilson Carla , Wilson James , Wong Quenna , Xu Huichun , Yanek Lisa , Yang Ivana , Yang Rongze , Zaghloul Norann , Zekavat Maryam , Zhang Yingze , Zhao Snow Xueyan , Zhao Wei , Zheng Xiuwen , Zhi Degui , Zhou Xiang , Zhu Xiaofeng , Zody Michael , Zoellner Sebastian , Abecasis Gonçalo R. , Boerwinkle Eric A. , Correa Adolfo , Cupples L. Adrienne , Kaplan Robert C. , Nickerson Deborah A. , North Kari E. , Psaty Bruce M. , Rotter Jerome I. , Rich Stephen S. , Tracy Russell P. , Vasan Ramachandran S. , Wilson James G. , Zhu Xiaofeng , Redline Susan ,   TOPMed Sleep Working Group, Cade Brian , Chen Han , Gharib Sina , Goodman Matthew , Gottlieb Daniel , Hale Lauren , Knutson Kristen , Lauderdale Diane , Lane Jacqueline , Lee Jiwon , Liang Jingjing , Lin Xihong , Liu Yaowu , Mei Hao , Mitchell Braxton , Ngo Debby , O’Connell Jeff , Ochs-Balcom Heather , Patel Sanjay , Purcell Shaun , Redline Susan , Rhodes Jessica , Saxena Richa , Shah Neomi , Sofer Tamar , Sul Jae Hoon , Sunyaev Shamil , Wang Heming , Wilson James , Zhang Man , Zhou Hufeng , Zhu Xiaofeng 
Published: August 2021

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.