We aimed to investigate whether DISC1 differentially modulates brain function during executive and memory processing, and morphology in regions relevant for depression and anxiety disorders (affective disorders).
We report the novel regulation of proteolytic processing of amyloid precursor protein (APP) by DISC1, a major risk factor for psychiatric illnesses, such as depression and schizophrenia.
Disrupted-In-Schizophrenia 1 (DISC1) was identified as a risk factor for psychiatric illness through its disruption by a balanced chromosomal translocation, t(1;11)(q42.1;q14.3), that co-segregates with schizophrenia, bipolar disorder and depression.
Cognitive measures of working memory (rs2793094, P=3.38 × 10(-4)), as well as lifetime history of depression (rs4658966, P=4.33 × 10(-4); rs12137417, P=4.93 × 10(-4)) and panic (rs12137417, P=7.41 × 10(-4)) were associated with DISC1 sequence variation.
These data are consistent with: (i) the high frequency of depression in the large Scottish family with a translocation disrupting DISC1; (ii) linkage disequilibrium analysis demonstrating haplotypes associated with relatively small increases in risk for bipolar disorder (<3-fold odds ratio).
This study demonstrates that Disc1 missense mutations in mice give rise to phenotypes related to depression and schizophrenia, thus supporting the role of DISC1 in major mental illness.