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 - Abecasis, Gonçalo R.
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
N1 - 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
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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 -