- This study investigated genetic determinants of daytime napping using data on all 452,633 individuals in the UK Biobank of European ancestry and a replication sample from 23andMe of 541,333 research participants of European ancestry
- Of 123 independent loci identified in the UK Biobank, 109 were tested in 23andMe and 61 were replicated; in a meta-analysis of UK Biobank and 23andMe (N=993,966), 94 of the 109 variants were genome-wide significant
- The variants occurred in established drug targets for sleep disorders (HCRTR1, HCRTR2), genes with roles in arousal (TRPC6, PNOC) and genes suggesting an obesity–hypersomnolence pathway (PNOC, PATJ)
- Genetic contributors to napping were shared with cardiometabolic diseases and traits, including body mass index, triglyceride levels and type 2 diabetes
- Mendelian randomization analysis showed potentially causal effects of more frequent daytime napping on higher diastolic blood pressure, higher systolic blood pressure and greater waist circumference
Whether habitual daytime napping affects the risk of cardiometabolic disease is a longstanding controversy. Cross-sectional studies have provided conflicting evidence about links between napping and blood pressure, obesity, metabolic traits and mortality.
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Interestingly, napping is a heritable behavior. A twin study published in Scientific Reports estimated its heritability to be 65%, similar to the heritability of nighttime sleep duration, and genome-wide association studies (GWAS) have detected multiple genetic loci for daytime napping.
Researchers at Mass General Brigham have now uncovered evidence that daytime napping and daytime sleepiness should be considered related, although distinct, features of the impaired arousal continuum, and that habitual daytime napping has causal effects on cardiometabolic health. Richa Saxena, PhD, principal investigator in the Department of Anesthesia and the Center for Genomic Medicine at Massachusetts General Hospital, and the Phyllis and Jerome Lyle Rappaport MGH Research Scholar 2017-2022; Marta Garaulet, PhD, MPH, of the Division of Sleep and Circadian Disorders at Brigham and Women's Hospital; and colleagues published their findings in Nature Communications.
Discovery and Validation of Genetic Loci for Napping
The research team conducted a GWAS of all 452,633 participants in the UK Biobank of European ancestry. These individuals answered extensive lists of questions at baseline when they were 40–69 years old, including a question about the frequency of daytime napping.
The team identified 123 distinct loci related to daytime napping, with genome-wide single nucleotide polymorphism (SNP)–based heritability estimated at 11.9%. By comparison, the SNP-based heritability of daytime sleepiness is 6.9%, according to a previous 2019 report in Nature Communications.
Variant effects were largely independent of body mass index (BMI) and sleep apnea, and the associations remained significant when the GWAS was restricted to healthier participants.
To replicate the lead loci, the team used data from 23andMe on 541,333 individuals of European ancestry who had provided data on daytime napping. Of 109 loci tested, 61 were replicated. In a meta-analysis of UK Biobank and 23andMe (N=993,966), 94 of the 109 lead variants were genome-wide significant.
Genetic Variants and Other Sleep Phenotypes
Several of the lead variants for daytime napping were located in or near genes with known effects on sleep–wake regulation:
- HCRTR1 and HCRTR2—Drug targets for narcolepsy and other sleep disorders (hypocretin/orexin pathway)
- TRPC6 and PNOC—Have roles in arousal
- PNOC and PATJ—Have effects on napping, daytime sleepiness and BMI, suggesting an obesity–hypersomnolence pathway
Genetic Contributors to Napping and Cardiometabolic Diseases
Using publicly available GWAS data for 257 traits, the researchers found modest positive correlations between napping and multiple anthropometric and cardiometabolic traits, including BMI, triglycerides and type 2 diabetes.
To further characterize shared genetic links, the researchers analyzed data from the Mass General Brigham Biobank on 23,561 participants of European ancestry. They generated a genome-wide polygenic score for napping and tested associations with 951 diseases. Three diseases were significantly associated with napping: essential hypertension, obesity and chronic nonspecific/nonalcoholic liver disease.
Causal Effect of Napping on Cardiometabolic Traits
The team also conducted a Mendelian randomization analysis, a statistical technique that uses genetic variants to distinguish correlation from causation in observational data. In this case, the 123 loci were used as genetic proxies for daytime napping. The researchers observed potentially causal effects of more frequent daytime napping on higher diastolic blood pressure, higher systolic blood pressure and greater waist circumference.
Implications for Sleep Drug Safety
Missense variants in HCRTR1 and HCRTR2 were not associated with any cardiovascular outcomes in a large GWAS or with any of 1,402 diseases defined in the UK Biobank, suggesting no excess cardiovascular risk of drugs that target orexin receptors. This is reassuring news because a dual orexin receptor antagonist is approved in the U.S. for the treatment of insomnia, with more such agents under investigation, and orexin receptor agonists are in development for narcolepsy.
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