Findings provide robust genetic evidence supporting a causal relationship between iRBD and the risk of multiple neurodegenerative diseases, highlighting the potential for shared pathophysiological mechanisms.
Abstract
Observational studies have proposed a link between isolated rapid eye movement sleep behavior disorder (iRBD) and several neurodegenerative diseases. We employed genome-wide linkage disequilibrium score regression (LDSC), standard two-sample Mendelian randomization (MR), and colocalization analysis to assess the causal links between iRBD and these neurodegenerative conditions. iRBD demonstrated a positive causal association with Alzheimer disease (odds ratio [OR] = 1.02, 95% confidence interval [CI]: 1.00–1.03, P = 1.10E−02), Parkinson disease (OR = 1.10, 95% CI: 1.03–1.16, P = 2.96E−03), and multiple sclerosis (OR = 1.09, 95% CI: 1.02–1.17, P = 1.61E−02). A strong positive genetic correlation with dementia with Lewy bodies was observed (rg = 1.6313, P = .0002), along with a causal association (OR = 1.45, 95% CI: 1.03–2.06, P = 3.53E−02), further supported by colocalization analysis. No significant causal relationship was identified between iRBD and amyotrophic lateral sclerosis (all P > .05). Additionally, reverse Mendelian randomization analyses did not reveal any causal relationships between the neurodegenerative diseases studied and iRBD. Our findings provide robust genetic evidence supporting a causal relationship between iRBD and the risk of multiple neurodegenerative diseases, highlighting the potential for shared pathophysiological mechanisms.
Genetic evidence supporting a causal role for depression in the etiology of late-onset AD is provided, a link not observed for other major psychiatric disorders tested and highlighted the specific importance of managing depression as a potential strategy for mitigating AD risk.
OBJECTIVE
This study applied two-sample Mendelian randomization (MR) to elucidate causal relationships between sleep-related phenotypes and childhood asthma risk.
METHODS
Instrumental variables for daytime napping, sleep disorders, chronotype, and fatigue were selected from European ancestry genome-wide association studies. Causal estimates were primarily derived using inverse-variance weighting (IVW), supplemented by sensitivity analyses including MR-Egger and MR-PRESSO. Instrument validity, heterogeneity, pleiotropy, and directionality were rigorously evaluated.
RESULTS
IVW results demonstrated that genetic susceptibility to daytime napping (OR = 1.76; 95% CI: 1.07-2.88; p < .05), sleep disorders (OR = 1.35; 95% CI: 1.12-1.61; p < .05), and frequent fatigue (OR = 2.94; 95% CI: 1.61-5.38; p < .05) significantly increased asthma risk, whereas morning chronotype was protective (OR = 0.76; 95% CI: 0.61-0.98; p = .015). Sensitivity analyses supported these findings, with no evidence of pleiotropy or reverse causation.
CONCLUSIONS
These results suggest that sleep behaviors causally influence childhood asthma risk and may represent modifiable targets for prevention and management.
Li Yin, Feifei Zhang, Fang Li et al.· Pediatric Allergy and Immuno...· 0 citations
Depression, hypertension, hypertension, and alcohol consumption were identified as significant mediators of the relationship between higher neuroticism and increased AD risk, suggesting that the neuroticism-AD relationship is unlikely to be causal.
N. Akbarian, M. Ebrahimi, F. D. Dos Santos et al.· medRxiv· 0 citations
Dementia poses a substantial global health burden, necessitating public health focus on modifiable risk factors. While sleep duration has been linked to dementia risk, studies specifically addressing middle-aged and older Chinese adults remain limited. Using cross-sectional (n=12,187) and longitudinal (n=9,030, 4-year follow-up) data from CHARLS, along with two-sample Mendelian randomization (MR), we examined associations between sleep duration and dementia, and causality between insomnia and dementia. We observed the strongest dementia risk among individuals reporting extreme sleep durations (<5h or >10h), both cross-sectional (OR=2.99, 95% CI: 2.47-3.62, P<0.001) and longitudinally (HR=1.55, 95% CI: 1.25-1.91, P<0.001). Restricted cubic spline analyses demonstrated a significant U-shaped dose-response association (P for nonlinearity <0.001). MR findings provided suggestive evidence for a potential causal effect of insomnia on dementia risk (OR=1.06, 95% CI: 1.01-1.13, P=0.029). Sensitivity analyses confirmed robustness. Optimizing sleep duration and managing insomnia may help reduce dementia risk in Chinese middle-aged and older adults.
Xiaoqing Tao, Shan Wang, Li He et al.· Neurosciences research· 0 citations
This study aimed to investigate the genetic causality between cataract (senile and other types) and psychiatric disorders using Mendelian randomization (MR). We performed a bidirectional 2-sample MR analysis using genome-wide association studies summary data. Primary analysis employed inverse-variance weighted, MR-Egger, weighted median, and weighted mode methods. Sensitivity analyses included Cochran Q, MR-pleiotropy residual sum and outlier, MR-Egger intercept, and leave-one-out tests to assess heterogeneity and pleiotropy. Forward MR analysis revealed a suggestive causal effect of other cataract on anxiety (inverse-variance weighted odds ratio [OR] = 0.99, 95% confidence interval: 0.98–1.00, P = .043), though unsupported by other methods. MR-Egger and weighted median suggested potential associations between other cataract and bipolar disorder (P < .05). No significant links were found between senile cataract and psychiatric disorders. Reverse MR analysis showed no consistent causal effects, except for anxiety disorder on other cataract (MR-Egger OR = 8.04, P = .040; weighted median OR = 2.99, P = .047). Sensitivity analyses confirmed robustness despite heterogeneity. This study provides evidence of a potential causal relationship between other cataract and anxiety, though findings were method-dependent. No significant associations were observed for senile cataract or most psychiatric disorders.
Background Neuropathic pain (NP) frequently co-occurs with sleep disorders, yet the causal relationship between the two remain unclear, necessitating further investigation to elucidate their intrinsic connection. Methods We conducted linkage disequilibrium score regression (LDSC), Mendelian randomization (MR), multivariable mendelian randomization (MVMR) and causal analysis using summary effect estimates (CAUSE) analyses based on genome-wide association study summary statistics of six NP subtypes (FinnGen R12) and six sleep traits (UK Biobank) to verify causal associations. Multi-method combined gene prioritization screening genes, with comprehensive sensitivity analyses and bias correction performed. Results Our analyses revealed that among all NP subtypes, only insomnia exerted a stable potential causal effect on sciatica. LDSC analysis revealed a significant positive genetic correlation between insomnia and sciatica (rg = 0.395, P < 0.0017). MR analyses demonstrated that insomnia significantly increased the risk of sciatica (OR = 3.15, 95% CI: 2.20–4.51, PIVW = 3.48E-10), with robust results confirmed by multiple sensitivity analyses. CAUSE further validated a positive causal association between insomnia and sciatica (OR = 3.899, 95% CI: 1.823–8.339, P = 0.003). MVMR proved the causal association remained significant after adjustment for psychiatric disorders (PIVW < 0.05). Heritability enrichment analysis indicated that the heritability of insomnia was mainly enriched in the central nervous system. And six potential pathogenic genes were screened via multiple integrated analytical methods. Among these candidates, EIF3KP1 and PPIP5K2 showed the strongest genetic evidence and were validated in the FinnGen database. Conclusion We identified a potential causal effect of insomnia on sciatica. The comorbidity of the two conditions may be regulated by genetic mechanisms associated with the central nervous system. EIF3KP1 and PPIP5K2 were prioritized as candidate genes, and further cellular and animal experiments are required to validate their potential as molecular targets for intervening in this comorbidity.
Shuyan Li, Xianmei Chen, Haiwen Cen et al.· Journal of Pain Research· 0 citations