Highlights
- •Whether daytime napping is causally associated with brain health remains elusive.
- •We studied the causal role of daytime napping on cognitive and neuroimaging outcomes.
- •We found a modest causal link between habitual napping and larger total brain volume.
Abstract
Objectives
Methods
Results
Conclusions
Keywords
Introduction
Grover S., Sharma, M. Sleep, pain, and neurodegeneration: a Mendelian Randomization Study. Frontiers in Neurology. 2022; 13. https://doi.org/10.3389/fneur.2022.765321.
Participants and methods
Sample
Never/rarely (n = 215,991) | Sometimes (n = 143,995) | Usually (n = 18,946) | |
---|---|---|---|
Covariates | |||
Age (mean/SD) | 55.4 (8.1) | 57.6 (7.9) | 59.4 (7.5) |
Sex (%female) | 59% | 50% | 33% |
Education years (mean/SD) | 15.4 (4.9) | 14.8 (5.1) | 14.3 (5.3) |
Townsend—most deprived quintile (%) | 17% | 20% | 24% |
Body Mass Index—kg/m2 (mean/SD) | 26.8 (4.5) | 27.9 (4.9) | 28.5 (5.2) |
Alcohol consumption—times per month-daily (%) | 46% | 42% | 44% |
Moderate physical activity—days (mean/SD) | 3.6 (2.3) | 3.6 (2.3) | 3.7 (2.3) |
Ever smoking—Current (%) | 9% | 11% | 14% |
Type-2 diabetes (%) | 3% | 6% | 10% |
Antihypertensives (%) | 16% | 24% | 32% |
Cardiovascular disease (%) | 5% | 8% | 14% |
Outcome variables | |||
Reaction time—milliseconds (mean/SD) | 548.8 (108.8) | 564.1 (116.4) | 579.1 (128.5) |
Visual memory—number of errors (mean/SD) | 4.0 (3.2) | 4.4 (3.6) | 4.0 (4.6) |
Hippocampal volume—cm3 (mean/SD) | 3.8 (0.4) | 3.8 (0.5) | 3.8 (0.4) |
Total brain volume—cm3 (mean/SD) | 1498.7 (72.8) | 1488.5 (72.7) | 1477.0 (73.5) |
Study design
Genotyping and quality control (QC) in UKB
Outcomes
Cognitive function measures
Neuroimaging parameters
Selection of genetic instruments
Main daytime napping genetic instrument
Additional daytime napping genetic instruments
Statistical analyses
Main analyses
Burgess S, Bowden J. Integrating summarized data from multiple genetic variants in Mendelian randomization: bias and coverage properties of inverse-variance weighted methods ArXiv151204486 Stat 2015. http://arxiv.org/abs/1512.04486. Accessed August 31, 2021.
Sensitivity analyses
- a.To ensure that our results were robust, we performed all of our MR analyses additionally using a 47- and 86-SNP daytime napping instrument, as described earlier. We confirmed a priori before implementing our analyses that these instruments were of adequate strength (via F-statistics).
- b.To mitigate potential issues with sample overlap between the discovery GWAS for daytime napping and our analytical dataset (both used UKB), we additionally performed our MR analyses using a reduced 17-SNP daytime napping instrument (Supplementary Table 3). This instrument consisted of the SNPs that were replicated (at P < 5 *10-8)23in an independent cohort (23andMe, n = 541,333), as an a priori F-statistic confirmed that it was suitable for use in our MR analyses (F = 67.1). We only performed these analyses for the cognitive function outcomes, as the overlap in samples between daytime napping and our neuroimaging analytical sample was<10%, and it is possible that analyses with a 17-SNP instrument in our subsample of ∼35,000 would result in imprecise MR estimates.
Testing of MR assumptions
- a.Associations between the genetic instrument and exposure instrumented (GWAS robust): this assumption was met, as the daytime napping variants that we instrumented here have been robustly associated with this phenotype in a recent very large-scale GWAS.
- b.No evidence of horizontal pleiotropy (no association between genetic instruments and the outcome, other than via the exposure under study): we tested this assumption by implementing MR-Egger and WME sensitivity analyses, as detailed above.
- c.No associations between genetic variants and confounders of the relationships under study: to assess this assumption, we regressed a number of common confounders on our main instrument (92 SNPs) and used a Bonferroni multiple testing correction of 0.05/92 = 0.0005. The list of confounders that we selected was based on the recent literature28and included: years of full-time education, deprivation (Townsend deprivation quintiles), smoking (ever/never/ex-smoker), physical activity (days of moderate activity for more than 10 minutes), body mass index (kg/m2), alcohol consumption (1-8 times per month/16 times per month-daily/rarely or never), prevalent type-2 diabetes (No/Yes), prevalent hypertension (No=not on antihypertensive medication and Yes=on antihypertensive medication), and prevalent cardiovascular disease (No/Yes).
Results
Sample characteristics
Main MR results
Associations between daytime napping and total brain, and hippocampal volumes using a 92-SNP genetic instrument
Associations between daytime napping and cognitive function using a 92-SNP genetic instrument
Sensitivity analyses
Associations between daytime napping and total brain, and hippocampal volumes using 47- and 86-SNP genetic instruments
Associations between daytime napping and cognitive function using 47- and 86-SNP genetic instruments
Association between daytime napping and cognitive function using a 17-SNP instrument with no sample overlap
Testing MR Assumption III
Associations between our main 92-SNP daytime napping genetic instrument and common confounders
Discussion
He J., Farias S., Martinez O., Reed B., Mungas D., DeCarli C. Differences in Brain Volume, Hippocampal Volume, Cerebrovascular Risk Factors, and Apolipoprotein E4 Among Mild Cognitive Impairment Subtypes | Dementia and Cognitive Impairment | JAMA Neurology | JAMA Network. 2009; 66. https://jamanetwork.com/journals/jamaneurology/article-abstract/798403. Accessed February 28, 2023.
Limitations
Conclusions
Acknowledgments
Declaration of conflicts of interest
Funding
Ethics approval
Appendix A. Supplementary material
Supplementary material
Supplementary material
Supplementary material
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