The immediate early gene, ARC, is a key regulator of protein synthesis-dependent synaptic plasticity. Synaptic plasticity functions in memory as well as in adaptive changes related to fear, anxiety, and reward. Dysfunction of synaptic plasticity is increasingly implicated in neuropsychiatric conditions including depression, schizophrenia and autism spectrum disorders. Our recent work links several SNPs in Arc to cognitive function. We tested whether ARC variants are associated with six measures of cognitive functioning in two healthy samples-the Norwegian Cognitive NeuroGenetics (NCNG) sample and the Swedish Betula sample. Of a total 71 ARC variants, 21 were nominally associated with human cognitive functions involving semantic knowledge, visuospatial abilities, delayed episodic memory, and general cognitive abilities (IQ).

Preliminary meta-analysis of large-scale genome-wide association studies' (GWAS) results across two neuropsychiatric conditions showing the most genetic overlap - SCZ and BP (http://www.med.unc.edu/pgc) - reveals a synergetic effect of two SNPs located in the regulatory downstream 3' region of the ARC gene (rs7465272 and rs7835613, p = 2.31e-06 and 9.01e-06 respectively). Adding MDD to the joint meta-analysis further reinforces the involvement of one of those SNPs in the susceptibility to neuropsychiatric conditions (rs7835613, p = 7.90e-06). Taking these findings together with known neuronal functions of the ARC gene, we hypothesize that its genetic variants may accentuate such common genetic architecture of cognitive abilities in neuropsychiatric conditions.

Our planned analyses:

1. Genetic association of ARC gene complex with cognitive function (cross-sectional and longitudinal examination)

1.1 ARC gene and cognitive functioning

AIM AND HYPOTHESIS

Here we plan to perform regression analyses to investigate whether common ARC variants are associated with cognition or other aspects of brain plasticity. Since previous studies are suggestive to this association, we hypothesize that various aspects of cognition , plasticity, and/or neuropsychiatric disorders will be associated with ARC variants.