Insomnia-Driven Hippocampal Atrophy: Evidence From Bidirectional Mendelian Randomization
Dandan Han1, Xiang Li2, Shaohua Zhao3
1Medical Imaging Center, Xuchang Central Hospital Affiliated to Henan University of Science and Technology Xuchang P.R. China.
Background:
Observational studies link insomnia to hippocampal atrophy, yet causal inference remains limited by confounding and reverse causality. While Mendelian randomization (MR) studies have explored sleep-brain associations, bidirectional causality between insomnia and hippocampal subfield volumes remains unaddressed.
Methods:
We conducted bidirectional two-sample MR using genome-wide association study (GWAS) summary data. Genetic instruments for insomnia (N = 462,341) and eight hippocampal volume imaging-derived phenotypes (IDPs; N ≈ 31,968-33,219) were selected (p < 5 × 10⁻⁸, LD r² < 0.001), with F-statistics > 10 ensuring robustness. Primary analyses employed inverse-variance weighted regression, supplemented by sensitivity analyses (MR-Egger, weighted median, MR-PRESSO) to assess pleiotropy and heterogeneity. Multiple testing was controlled using Benjamini-Hochberg FDR.
Results:
Forward MR revealed inverse associations between genetically proxied insomnia and six of eight hippocampal phenotypes: T1 left hippocampus volume (OR = 0.62, 95% CI = 0.43-0.89; P FDR = 0.014), left hippocampus gray matter volume (OR = 0.63, 95% CI = 0.47-0.84; P FDR = 0.008), right hippocampus gray matter volume (OR = 0.69, 95% CI = 0.49-0.98; P FDR = 0.035), left and right hippocampal volumes from automated subcortical segmentation (ORs = 0.60, 95% CI = 0.42-0.86, P FDR = 0.010; and 0.71, 0.51-0.99, P FDR = 0.037), and right whole-hippocampus volume from subfield segmentation (OR = 0.61, 95% CI = 0.43-0.86; P FDR = 0.010). Sensitivity analyses supported robustness; reverse MR detected no evidence of effects of hippocampal volumes on insomnia (P FDR = 1).
Conclusions:
Genetically proxied insomnia shows strong genetic evidence consistent with a causal reduction in hippocampal volumes. Clinically, early intervention in insomnia, particularly through cognitive-behavioral therapy for insomnia, may help preserve hippocampal health. This study highlights the importance of addressing insomnia as a public health priority. Future research should investigate the underlying biological mechanisms and incorporate more diverse cohorts to enhance the generalizability of these findings.
Insights
Genetically proxied insomnia causally reduces hippocampal volumes, suggesting early intervention may preserve brain health. Addressing insomnia is crucial for public health and cognitive well-being.
Area of Science:
- Neuroscience
- Genetics
- Public Health
Background:
- Observational studies suggest a link between insomnia and hippocampal atrophy.
- Causal inference is limited by confounding and reverse causality.
- Bidirectional causality between insomnia and hippocampal subfield volumes remains unaddressed.
Purpose of the Study:
- To investigate the bidirectional causal relationship between insomnia and hippocampal volumes using Mendelian randomization.
- To determine if genetic predisposition to insomnia affects hippocampal subfield volumes.
- To assess if hippocampal volumes influence the risk of insomnia.
Main Methods:
- Conducted a bidirectional two-sample Mendelian randomization (MR) study.
- Utilized genome-wide association study (GWAS) summary data for insomnia and eight hippocampal volume imaging-derived phenotypes (IDPs).
- Employed inverse-variance weighted regression and sensitivity analyses, controlling for multiple testing with Benjamini-Hochberg FDR.
Main Results:
- Forward MR showed genetically proxied insomnia was inversely associated with six of eight hippocampal phenotypes, indicating reduced volumes.
- Sensitivity analyses confirmed the robustness of these findings.
- Reverse MR found no evidence that hippocampal volumes causally affect insomnia.
Conclusions:
- Insomnia has a causal effect on reducing hippocampal volumes.
- Early intervention for insomnia, such as cognitive-behavioral therapy, may help preserve hippocampal health.
- Addressing insomnia is a public health priority, warranting further research into biological mechanisms and generalizability.
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