Sleep, pain, and neurodegeneration: A Mendelian randomization study

Objective To examine whether sleep and pain-related traits have a causal effect on the risk of neurodegeneration. Design Two-sample Mendelian randomization using an inverse-variance weighted (IVW) estimate of the summary effect estimates. Setting Genetic data on sleep and pain-related traits and neurodegenerative disorders (NDD) from various cohorts comprising individuals predominantly of European ancestry. Participants Participants from the International Sleep Genetic Epidemiology Consortium (ISGEC), UK Biobank sleep and chronotype research group, International Genomics of Alzheimer’s patients (IGAP), project MinE, International Age-related Macular Degeneration Consortium (IAMDGC), International Multiple Sclerosis Genetics Consortium (IMSGC), International Parkinson’s Disease Genomics Consortium (IPDGC) Exposures Self-reported chronotype (CHR), morning preference (MP), insomnia symptoms (INS), sleep duration (SP), short sleep (SS), long sleep (LS), and multisite chronic pain (MCP) Main outcome measures Age-related macular degeneration (AMD), Alzheimer’s disease (AD), Amyotrophic lateral sclerosis (ALS), Multiple sclerosis (MS), and Parkinson’s disease (PD) Results We considered a threshold of P=0.00142 as significant accounting for multiple testing, and P<0.05 was considered to be suggestive evidence for a potential association. Using direct MR, MP was observed as the strongest risk factor for AMD (OR IVW = 1.19, 95% CI 1.08, 1.32, P = 0.00073). We observed suggestive evidence of influence of different sleep traits on neurodegeneration: CHR on AMD (OR IVW = 1.27, 95% CI 1.08, 1.49, P = 0.0034), SS on AD (OR IVW 1.26, 95% CI 1.08, 1.46, P = 0.0044), and INS on ALS (OR IVW 1.55, 95% CI 1.12, 2.14, P = 0.0123). The association of SS with AD was, however, lost after the exclusion of overlapping UKB samples. Using pain as exposure, our study failed to observe any role of pain in neurodegeneration. Results were largely robust to reverse causal analyses and sensitivity analyses accounting for horizontal pleiotropy. Conclusions Our study highlighted the role of morning preference as a risk factor for AMD and provided suggestive evidence of different sleep traits on a wide spectrum of neurodegenerative diseases.