0031 Whole genome sequence analyses for Excessive Daytime Sleepiness in the NHLBI TOPMed Program

Abstract

Abstract 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< 1x10-7). In gene-based burden test, we did not identify any gene significantly associated with the ESS after correcting for multiple comparisons (p< 2x10-6). Suggestive significant evidence was observed at OR1A2 (consisting of 41 missense variants; p-value=1.65x10-5), 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 (if any) R01HL153814 (to H.W.), NHLBI R35HL135818 (to S.R.).