Total Brain Volumetric Measures and Schizophrenia Risk: A Two-Sample Mendelian Randomization Study

Area of Science:

• Neuroscience
• Psychiatry
• Genetics

Background:

• Schizophrenia (SCZ) is a complex psychiatric disorder with a known heritable component.
• Abnormalities in total brain volumetric measures (TBVMs) are observed in SCZ patients, but their causal role remains unclear.

Purpose of the Study:

• To investigate the potential causal relationship between TBVMs and the risk of developing SCZ using Mendelian randomization (MR).

Main Methods:

• A Mendelian randomization study utilizing genome-wide association study (GWAS) summary statistics for TBVMs (n=33,224) and SCZ (n=150,064).
• Employed inverse variance weighted (IVW) as the primary MR method, supplemented by MR-Egger, weighted median, and other methods for robustness.
• Assessed pleiotropy and heterogeneity using MR-Egger intercept, MR-PRESSO, and heterogeneity tests.

Main Results:

• No significant causal association was detected between any TBVM and SCZ risk across the applied MR methods.
• Instrumental variables showed no evidence of significant pleiotropy or heterogeneity.

Conclusions:

• Alterations in total brain volumetric measures are not causally linked to the risk of schizophrenia.
• This finding helps clarify the etiological pathways of SCZ, suggesting that observed volumetric differences may be consequences rather than causes.