Genome-wide association study of regional brain volume suggests involvement of known psychiatry candidate genes, identified new candidates for psychiatric disorders and points to potential modes of their action
Though most psychiatric disorders are highly heritable, it has been hard to identify genetic risk factors
involved, which are most likely of small individual effect size. A possible way to aid identification of
risk genes is the use of intermediate phenotypes. These are supposed to be closer to the biological
substrate(s) of the disorder than psychiatric diagnoses, and therefore less genetically complex.
Intermediate phenotypes can be defined e. g. at the level of brain function and of regional brain
structure. Both are highly heritable, and regional brain structure is linked to brain function.
Within the Brain Imaging Genetics (BIG) study at the Radboud University Nijmegen (Medical Centre)
we performed a genome-wide association study (GWAS) in 1000 of the currently 1400 healthy study
participants. For all BIG participants, structural MRI brain images were available. Gray and white
matter volumes were determined by brain segmentation using SPM software. FSL-FIRST was used
to assess volumes of specific brain structures. Genotyping was performed on Affymetrix 6.0 arrays.
Results implicate known candidates from earlier GWAS and candidate gene studies in mental
disorders in the regulation of regional brain structure. E. g. polymorphisms in CDH13, featuring
among the top-findings of GWAS in disorders including ADHD, addiction and schizophrenia, were
found associated with amygdala volume. The ADHD candidate gene SNAP25 was found associated
with total brain volume.
In conclusion, the use of intermediate phenotypes based on (subcortical) brain volumes may shed
more light on pathways from genes to diseases, but can also be expected to facilitate gene
identification in psychiatric disorders.
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