Investigating Bidirectional Causal Relationships Between Imaging-Derived Brain Phenotypes and Sedative-Hypnotic Use...

Area of Science:

• Neuroimaging Genetics
• Psychiatric Disorders
• Addiction Research

Background:

• Sedative-hypnotic use disorder (SHUD) poses significant public health challenges due to high abuse potential.
• The neurobiological underpinnings of individual susceptibility to SHUD are not well understood.

Purpose of the Study:

• To investigate the causal relationship between brain imaging-derived phenotypes (IDPs) and SHUD risk using a large-scale, bidirectional Mendelian randomization (MR) study.
• To identify specific brain structural and functional characteristics associated with SHUD susceptibility.

Main Methods:

• Utilized genome-wide association study (GWAS) summary statistics for 3,935 brain IDPs from UK Biobank and SHUD data from FinnGen.
• Employed inverse-variance weighted (IVW) method with sensitivity analyses (MR-Egger, weighted median, MR-PRESSO) for causal effect estimation.
• Applied Benjamini-Hochberg false discovery rate (FDR) correction for multiple testing.

Main Results:

• Identified 34 brain IDPs causally associated with SHUD risk.
• Increased SHUD susceptibility linked to higher cortical thickness in temporal regions, altered white-to-grey matter contrast in insula and parahippocampal gyrus.
• Reduced risk associated with larger brainstem volume, better white matter integrity in the cingulum, and specific functional connectivity patterns (salience network, visual-somatomotor networks).

Conclusions:

• Established a causal link between SHUD susceptibility and specific brain structural and functional traits, particularly involving the temporal-limbic and salience systems.
• Findings provide novel mechanistic insights into the neurobiology of SHUD.
• Identified potential neuroimaging biomarkers for risk stratification and therapeutic target development in SHUD.