Whole genome sequence analyses for Excessive Daytime Sleepiness in the NHLBI TOPMed Program
| Submitted by | Wang, Heming
|
|---|---|
| Authors | Yiyan Zhang1, Nuzulul Kurniansyah1, Pavithra Nagarajan1, Han Chen2,3, Shaun M Purcell1,4,5, Richa Saxena1,4,5,6, Xiaofeng Zhu7, Brian Cade1,4, Tamar Sofer1,4, Susan Redline1,4, Heming Wang1,4,5, TOPMed Sleep Working Group
1Division of Sleep and Circadian Disorders, Brigham and Women’s Hospital, Harvard Medical School, 221 Longwood Avenue, Boston, MA, 02115, USA 2Human Genetics Center, Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA 3Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA 4Division of Sleep Medicine, Harvard Medical School, Boston, MA, 02115, USA 5Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, 02142, USA 6Center for Genomic Medicine and Department of Anesthesia, Pain, and Critical Care Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA 7Department of Population and Quantitative Health Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA |
| Name and Date of Professional Meeting | SLEEP (June 3, 2023)
|
| Associated paper proposal(s) | |
| Working Group(s) | |
| Abstract Text |
Introduction: Excessive daytime sleepiness is associated with multiple sleep, cardiometabolic, and neuropsychiatric disorders. Previous genome-wide association studies (GWAS) of daytime sleepiness using a single question in European population revealed associations for multiple genes in central nervous pathways. However, findings are still limited and may not be generalizable to other populations. In this study, we performed the first whole-genome sequence (WGS) analyses for Epworth Sleepiness Scale (ESS) in the NHLBI Trans-Omics for Precision Medicine (TOPMed) program.
Methods: This study includes 15,201 individuals of diverse race and ethnic backgrounds from seven cohorts in the TOPMed. We performed GWAS of single common variants (MAF>0.01) and gene-based burden tests of low-frequency and rare functional variants (loss of function and missense; MAF<0.05). We adjusted for age, sex, body mass index (BMI), study, race/ethnicity, and genetic relatedness using linear mixed effects models implemented in the GENESIS R package. Results: This sample included 43.8% males with a mean age of 54.9 years and BMI 29.6kg/m2, of whom 21.3% were classified with excessive daytime sleepiness (ESS≥10). In single variant test, we identified one novel genomic locus at rs60249969 (on CELF2) significantly associated with ESS (p-value=3.91x10-8). Suggestive significant associations were observed at 5 novel loci that overlapped with PDE7A/DNAJC5B, AHI1/PDE7B, KCNH7, F5, and FBXL17 (p<110-7). In gene-based burden test, we did not identify any gene significantly associated with the ESS after correcting for multiple comparisons (p<210-6). Suggestive significant evidence was observed at OR1A2 (consisting of 41 missense variants; p-value=1.6510-5), an olfactory receptor gene differentially expressed in choroid plexus in the brain implicated in neurodegenerative diseases. Conclusion: In our investigation of common and rare variant associations with excessive daytime sleepiness as assessed by the ESS, we identified one significant and several suggestive novel loci that mapped to genes highly expressed in brain tissues, which may have implications on sleep wake control system. Our next step will include replication analyses using independent imputed samples. Support: R01HL153814 (to H.W.), R35HL135818 (to S.R.). |
Back to top
