@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 = "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",
}