Genome-wide gene-sleep interaction study identifies novel lipid loci in 732,564 participants.

Summary

Across 55 cohorts (n=732,564), short or long sleep modified genetic effects on HDL-C, LDL-C, and TG, yielding 17 significant loci in interaction or joint tests. Pathway signals implicated vitamin D receptor-related biology in sleep-associated lipid regulation.

Key Findings

• Meta-analysis across 55 cohorts (n=732,564) identified 17 loci where sleep duration modified genetic effects on lipids (9 short-sleep, 8 long-sleep).
• Interaction testing discovered 10 novel loci; joint tests integrating main and interaction effects further expanded discovery.
• Pathway signals implicated vitamin D receptor biology in sleep-associated lipid regulation.

Clinical Implications

While not immediately actionable, results support incorporating sleep assessment in cardiometabolic risk models and motivate trials testing pathway-targeted interventions (e.g., vitamin D signaling) in sleep-disturbed populations.

Limitations

• Predominantly European ancestry (87%), limiting generalizability.
• Sleep duration definitions rely on cohort-specific standardized extremes; measurement heterogeneity likely.
• Observational design precludes causal inference; functional validation is pending.

Future Directions

Replicate in non-European ancestries, integrate objective sleep measures (actigraphy), and perform functional studies to validate candidate genes and pathways (e.g., vitamin D receptor signaling).