Whole-Genome Association Analyses of Sleep-disordered Breathing Phenotypes in the NHLBI TOPMed Program

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.; Hillman, D. R.; Mukherjee, S.; Palmer, L. J.; Stone, K. L.; Tranah, G. J.; NHLBI Trans-Omics for Precision Medicine (TOPMed),; Abecasis, G.; Boerwinkle, E.; Correa, A.; Cupples, L. A.; Kaplan, R. C.; Nickerson, D. A.; North, K. E.; Psaty, B. M.; Rotter, J. I.; Rich, S. S.; Tracy, R. P.; Vasan, R. S.; Wilson, J. G.; Zhu, X.; Redline, S.; TOPMed Sleep Working Group,

doi:10.1101/652966

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bioRxiv · 10.1101/652966

Whole-Genome Association Analyses of Sleep-disordered Breathing Phenotypes in the NHLBI TOPMed Program

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Abstract

Sleep-disordered breathing (SDB) is a common disorder associated with significant morbidity. Through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program we report the first whole-genome sequence analysis of SDB. We identified 4 rare gene-based associations with SDB traits in 7,988 individuals of diverse ancestry and 4 replicated common variant associations with inclusion of additional samples (n=13,257). We identified a multi-ethnic set-based rare-variant association (p = 3.48 x 10-8) on chromosome X with ARMCX3. Transcription factor binding site enrichment identified associations with genes implicated with respiratory and craniofacial traits. Results highlighted associations in genes that modulate lung development, inflammation, respiratory rhythmogenesis and HIF1A-mediated hypoxic response.

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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., Hillman, D. R., Mukherjee, S., Palmer, L. J., Stone, K. L., Tranah, G. J., NHLBI Trans-Omics for Precision Medicine (TOPMed),, Abecasis, G., Boerwinkle, E., Correa, A., Cupples, L. A., Kaplan, R. C., Nickerson, D. A., North, K. E., Psaty, B. M., Rotter, J. I., Rich, S. S., Tracy, R. P., Vasan, R. S., Wilson, J. G., Zhu, X., Redline, S., TOPMed Sleep Working Group,. 2019-06-03. Whole-Genome Association Analyses of Sleep-disordered Breathing Phenotypes in the NHLBI TOPMed Program. https://doi.org/10.1101/652966

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