Evaluating the role of rare genetic variation in sleep duration

Abstract

Objectives: To explore the roles of rare and high-impact variants in sleep duration.

Design: Based on the recently released UK Biobank 200k exome dataset, an exome-wide association study was conducted to detect rare variants (minor allele frequency <0.01) contributing to sleep duration. Variant annotations were performed by the software tool ANNOVAR. Gene-based burden tests of sleep duration were conducted by the SKAT R-package. After quality control, 137,047 subjects were included in this study. CAUSALdb database was used to explore the related mental traits of identified genes.

Results: We detected 730,572 variants with MAF < 1%, including 3873 frameshift variants, 3977 nonframeshift variants, 449,632 nonsynonymous variants, 1293 startloss variants, 10,254 stopgain variants, 413 stoploss variants, 261,130 synonymous variants, and 3102 variants are annotated as unknown. The burden test of exonic variants detected two exome-wide significant associations for sleep duration including TMIE at 3p21.31 (P_{Bonferroni adjusted} = 0.015) and ZIC2 at 13q32.3 (P_{Bonferroni adjusted} = 0.047). There are only nonsynonymous contained in TMIE; as for ZIC2, we detected 2 annotations of variants: nonsynonymous (P_{Bonferroni adjusted} =2.04 × 10^-4) and nonframeshift (P_{Bonferroni adjusted} =0.85). TMIE and ZIC2 were reported to be associated with several mental traits, such as chronotype, depression, and brain natriuretic peptide in published study.

Conclusion: This study reported 2 novel candidate genes for a sleep duration, supporting the roles of rare genetic variants in the regulation of sleep duration.

Keywords: Burden test; Exome-wide association study; Rare genetic variation; Sleep duration; UK Biobank exome-sequencing.