The relationship between sleep duration, cognition and dementia: a Mendelian randomization study

Abstract

Background: Short and long sleep duration have been linked with poorer cognitive outcomes, but it remains unclear whether these associations are causal.

Methods: We conducted the first Mendelian randomization (MR) study with 77 single-nucleotide polymorphisms (SNPs) for sleep duration using individual-participant data from the UK Biobank cohort (N = 395 803) and summary statistics from the International Genomics of Alzheimer's Project (N cases/controls = 17 008/37 154) to investigate the potential impact of sleep duration on cognitive outcomes.

Results: Linear MR suggested that each additional hour/day of sleep was associated with 1% [95% confidence interval (CI) = 0-2%; P = 0.008] slower reaction time and 3% more errors in visual-memory test (95% CI = 0-6%; P = 0.05). There was little evidence to support associations of increased sleep duration with decline in visual memory [odds ratio (OR) per additional hour/day of sleep = 1.10 (95% CI = 0.76-1.57); P = 0.62], decline in reaction time [OR = 1.28 (95% CI = 0.49-3.35); P = 0.61], all-cause dementia [OR = 1.19 (95% CI = 0.65-2.19); P = 0.57] or Alzheimer's disease risk [OR = 0.89 (95% CI = 0.67-1.18); P = 0.41]. Non-linear MR suggested that both short and long sleep duration were associated with poorer visual memory (P for non-linearity = 3.44e-9) and reaction time (P for non-linearity = 6.66e-16).

Conclusions: Linear increase in sleep duration has a small negative effect on reaction time and visual memory, but the true association might be non-linear, with evidence of associations for both short and long sleep duration. These findings suggest that sleep duration may represent a potential causal pathway for cognition.

Keywords: Mendelian randomization; Sleep duration; cognition; dementia.

Figure 1.

Study design. N, number of observations; HES, Hospital Episode Statistics; SNP, single-nucleotide polymorphism; MR, Mendelian randomization; G-X, genetic association of instrument (SNP) with exposure; G-Y, genetic association of instrument (SNP) with outcome; IGAP, International Genomics of Alzheimer’s Project.

Figure 2.

Results from observational and Mendelian randomization analyses. Numbers represent effect size per additional hour/day of sleep duration; Exp(Beta), exponentiated beta (represents multiplicative effect size, e.g. an exponentiated beta of 1.03 in reaction time represents an estimated 3% increased/slower reaction time); P Pleiotropy, P-value for overall horizontal pleiotropic effect as indicated by the intercept from MR-Egger regression; Obs-unadjusted, unadjusted observational analysis; Obs-adjusted, observational analysis adjusted for age, sex, socio-economic status, qualification, employment, smoking status, alcohol-intake frequency, body mass index, hypertension, co-morbidities and use of sleep-inducing medication; MR-IVW, Mendelian randomization, inverse-variance-weighted; MR-WME, Mendelian randomization, weighted median estimator.

Figure 3.

Non-linear Mendelian randomization results with piecewise linear method using three strata of sleep duration conditioned on the genetic instruments. Annotated numbers [black dots (grey vertical lines)] represent localized average causal effect (95% confidence interval) in each stratum; white dots, mean sleep duration used as reference point (X ref); P quadratic/Cochran Q, P-value for non-linearity from quadratic/Cochran Q test; Ln (incorrect matches + 1), natural log of [number of incorrect matches (errors made) in visual-memory test + 1]; Ln (ms), natural log milliseconds of reaction time.