DISC1 gene and affective psychopathology: A combined structural and functional MRI study

Abstract

The gene Disrupted-In-Schizophrenia-1 (DISC1) has been indicated as a determinant of psychopathology, including affective disorders, and shown to influence prefrontal cortex (PFC) and hippocampus functioning, regions of major interest for affective disorders. 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). 128 participants, with (n = 103) and without (controls; n = 25) affective disorders underwent genotyping for Ser704Cys (with Cys-allele considered as risk-allele) and structural and functional (f) Magnetic Resonance Imaging (MRI) during visuospatial planning and emotional episodic memory tasks. For both voxel-based morphometry and fMRI analyses, we investigated the effect of genotype in controls and explored genotypeXdiagnosis interactions. Results are reported at p < 0.05 FWE small volume corrected. In controls, Cys-carriers showed smaller bilateral (para)hippocampal volumes compared with Ser-homozygotes, and lower activation in the anterior cingulate cortex (ACC) and dorsolateral PFC during visuospatial planning. In anxiety patients, Cys-carriers showed larger (para)hippocampal volumes and more ACC activation during visuospatial planning. In depressive patients, no effect of genotype was observed and overall, no effect of genotype on episodic memory processing was detected. We demonstrated that Ser704Cys-genotype influences (para)hippocampal structure and functioning the dorsal PFC during executive planning, most prominently in unaffected controls. Results suggest that presence of psychopathology moderates Ser704Cys effects.

Imaging microstructure with diffusion and susceptibility MR: neuronal density correlation in Disrupted‐in‐Schizophrenia‐1 mutant mice

“…41 Later, a smaller bilateral hippocampal volume was also reported in subjects with DISC1 variant. 4 We speculate that the increase in neuronal density may result partly from a decrease of hippocampal volume, similar to that observed in Alzheimer's disease. 14 A previous study that investigated both structural and functional changes associated with DSIC1 reported reduced hippocampal gray matter volume and altered engagement of the hippocampus during several cognitive tasks.…”

“…2 In a recent study of transgenic mice with inducible expression of mutant human DISC1 (hDISC1), abnormalities limited to forebrain regions, including cerebral cortex, hippocampus and striatum, were reported. 3 The most consistent imaging findings of anatomical abnormalities in brains of human subjects with DISC1 genetic variants include lateral and third ventricular enlargement, medical temporal lobe volume reduction, especially the hippocampal volume, [4][5][6] and cortical thinning. 7 MRS studies also reported decreased N-acetylaspartate, elevated glutamatergic indices in frontal cortex and basal, and elevated glutamate/glutamine in the hippocampus.…”

Prefrontal mechanisms of comorbidity from a transdiagnostic and ontogenic perspective

“…These genes are also associated with various structural neuroimaging phenotypes of the PFC (Kamiya et al, 2006; Porteous, Thomson, Brandon, & Millar, 2006). More specifically, DISC1 Cys-allele carriers and BDNF Met-allele carriers both show reduced PFC volumes, and decreased PFC activation during EF tasks, compared to noncarriers (Hashimoto et al, 2006; Kim, Kang, et al, 2013; Opmeer et al, 2015; Pezawas et al, 2004; Prata et al, 2008) suggesting a link between specific allelic variations and individual differences in PFC structure and function.…”

Fifteen years of NESDA Neuroimaging: An overview of results related to clinical profile and bio-social risk factors of major depressive disorder and common anxiety disorders

“…DISC-1: Finally, the last candidate gene for (vulnerability for) affective disorders examined within the NESDA MRI project was the Disrupted-In-Schizophrenia-1(DISC1) gene (Opmeer et al, 2015). Previous studies found associations suggesting that the DISC1-genotype Ser704Cys (with the Cys-allele as risk-allele) was involved in functioning and structure of hippocampal, ACC and prefrontal regions, regions of major interest for affective disorders.…”

“…However, no previous study examined associations for the various regions at the same time. Opmeer et al (2015) therefore studied the effects of Ser704Cys-genotype on function and structure of the ACC, dorsolateral prefrontal cortex, and hippocampus in both patients and controls from NESDA. It was hypothesized that Cys-carriers would show smaller grey matter volumes and less activation in these regions of interest during executive planning and episodic memory.…”