Common risk alleles for schizophrenia within the major histocompatibility complex predict white matter microstructure

Area of Science:

• Neuroscience
• Genetics
• Psychiatry

Background:

• Complement genes play a role in brain development and schizophrenia risk.
• Schizophrenia is associated with alterations in white matter microstructure.

Purpose of the Study:

• To investigate the association between schizophrenia risk variants in complement genes and white matter microstructure in tracts connecting to the frontal lobe.
• To identify specific genomic regions and microstructural metrics affected by these risk variants.

Main Methods:

• Analysis of common risk variants within complement genes and intergenic regions.
• Correlation with diffusion tensor imaging (DTI) metrics, specifically axonal density and orientation dispersion index.
• Focus on white matter tracts connecting frontal cortex to other brain regions.

Main Results:

• Risk alleles within the complement gene set and intergenic regions significantly predicted axonal density.
• The Major Histocompatibility Complex (MHC) region on chromosome 6 was identified as a key driver of these associations.
• No significant associations were found for the orientation dispersion index, indicating changes in axonal packing but not coherence.

Conclusions:

• Common risk alleles within the MHC region, including complement-related variants, influence axonal packing in specific white matter tracts.
• Altered axonal packing is a potential neurobiological mechanism underlying schizophrenia risk.
• These findings provide insights into the genetic architecture of schizophrenia and brain development.