Pathway analysis of genetic markers associated with a functional MRI faces paradigm implicates polymorphisms in calcium responsive pathways

Morten Mattingsdal (Lead / Corresponding author), Andrew Anand Brown, Srdjan Djurovic, Ida Elken Sønderby, Andres Server, Ingrid Melle, Ingrid Agartz, Eivind Hovig, Jimmy Jensen, Ole A. Andreassen

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)

Abstract

Several lines of evidence suggest that common polygenic variation influences brain function in humans. Combining high-density genetic markers with brain imaging techniques is constricted by the practicalities of collecting sufficiently large brain imaging samples. Pathway analysis promises to leverage knowledge on function of genes to detect recurring signals of moderate effect. We adapt this approach, exploiting the deep information collected on brain function by fMRI methods, to identify molecular pathways containing genetic variants which influence brain activation during a commonly applied experiment based on a face matching task (n=246) which was developed to study neural processing of faces displaying negative emotions. Genetic markers moderately associated (p<10(-4)) with whole brain activation phenotypes constructed by applying principal components to contrast maps, were tested for pathway enrichment using permutation based methods. The most significant pathways are related to post NMDA receptor activation events, driven by genetic variants in calcium/calmodulin-dependent protein kinase II (CAMK2G, CAMK2D) and a calcium-regulated nucleotide exchange factor (RASGRF2) in which all are activated by intracellular calcium/calmodulin. The most significant effect of the combined polygenic model were localized to the left inferior frontal gyrus (p=1.03 × 10(-9)), a region primarily involved in semantic processing but also involved in processing negative emotions. These findings suggest that pathway analysis of GWAS results derived from principal component analysis of fMRI data is a promising method, to our knowledge, not previously described.

Original languageEnglish
Pages (from-to)143-149
Number of pages7
JournalNeuroImage
Volume70
DOIs
Publication statusPublished - 15 Apr 2013

Keywords

  • Adult
  • Brain/metabolism
  • Calcium/physiology
  • Face
  • Female
  • Genetic Markers
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Mental Disorders/genetics
  • Metabolic Networks and Pathways/genetics
  • Polymorphism, Single Nucleotide

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