Pathway analysis of genetic markers associated with a functional MRI faces paradigm implicates polymorphisms in...

Area of Science:

• Neurogenetics
• Cognitive Neuroscience

Background:

• Polygenic variation is increasingly recognized to influence human brain function.
• Integrating genetic data with brain imaging is challenging due to sample size limitations.

Purpose of the Study:

• To adapt pathway analysis for identifying molecular pathways associated with genetic variants affecting brain activation.
• To investigate brain activation during negative emotional face processing using functional magnetic resonance imaging (fMRI).

Main Methods:

• Applied pathway enrichment analysis to genetic markers associated with brain activation phenotypes derived from fMRI data.
• Utilized principal component analysis (PCA) on contrast maps from a face matching task (n=246).
• Tested for pathway enrichment using permutation-based methods for genetic markers with p<10(-4).

Main Results:

• Identified significant pathways related to post-NMDA receptor activation events.
• Found genetic variants in CAMK2G, CAMK2D, and RASGRF2 genes driving these pathways.
• Localized the most significant polygenic effect to the left inferior frontal gyrus, a region involved in semantic processing and emotion.

Conclusions:

• Pathway analysis of GWAS results combined with PCA of fMRI data is a novel and promising method.
• This approach can identify molecular pathways influencing brain activation, particularly in regions like the left inferior frontal gyrus.
• Findings highlight the role of calcium/calmodulin-dependent pathways in neural processing of negative emotions.