Genome-Wide Association Analyses in 128,266 Individuals Identifies New Morningness and Sleep Duration Loci.
Level 3 - non-randomized controlled study
Cross-sectional genetic association study and meta-analysis across large cohorts (graded by non-clinical design analogy).
PubMed 27494321 · doi:10.1371/journal.pgen.1006125
What was done
Researchers conducted genome-wide association studies (GWAS) for self-reported chronotype (morningness vs. eveningness) and self-reported sleep duration in 128,266 white British participants from the UK Biobank. Findings were tested for replication in 89,283 participants from 23andMe. Genetic correlations and Mendelian randomization analyses were also performed to assess causal relationships with body mass index (BMI) and type 2 diabetes.
What was found
Sixteen loci were associated with chronotype at genome-wide significance (P < 5x10⁻⁸) in the UK Biobank discovery cohort, including variants near circadian genes RGS16 (OR 1.21, 95% CI [1.15, 1.27], P = 3x10⁻¹²) and PER2 (OR 1.09, 95% CI [1.06, 1.12], P = 4x10⁻¹⁰). Combined with replication and reciprocal analyses in 23andMe, 22 loci reached genome-wide significance for chronotype. For sleep duration, the study replicated a PAX8 signal (2.6 min/allele, 95% CI [1.9, 3.2], P = 5.7x10⁻¹⁶) and identified two novel VRK2 signals (2.0 min/allele, 95% CI [1.3, 2.7], P = 1.2x10⁻⁹; and 1.6 min/allele, 95% CI [1.1, 2.2], P = 7.6x10⁻⁹), bringing the total to three loci. Genetic correlations were observed between BMI and chronotype (rG = 0.056, P = 0.05), undersleeping (rG = 0.147, P = 1x10⁻⁵), and oversleeping (rG = 0.097, P = 0.04). However, Mendelian randomization analyses provided no consistent evidence of causal links between BMI or type 2 diabetes and chronotype or sleep duration.
Why it matters
This study expands the known genetic architecture of human circadian preference and sleep duration by identifying 22 chronotype and 3 sleep duration loci, providing biological candidate pathways such as RGS16 and VRK2.
Limits
The discovery cohort was restricted to individuals of white British ancestry, limiting generalizability across other ancestries. Phenotypes for both chronotype and sleep duration relied exclusively on self-report rather than objective actigraphy or polysomnography. Furthermore, Mendelian randomization analyses had limited statistical power to rule out small causal effects between sleep traits, BMI, and type 2 diabetes.
Cited by
- supports Approximately 20 percent of the population has an early-bird chronotype, meaning they are genetically hardwired to wake up and go to sleep early.