An integrated molecular landscape implicates the regulation of dendritic spine formation through insulin-related signalling in obsessive–compulsive disorder

Abstract

IntroductionAttention-deficit/hyperactivity disorder (ADHD) is a common neuropsychiatric disorder characterized by developmentally inappropriate impulsive, hyperactive and/or inattentive symptoms. 1 Previous MRI studies have reported smaller total brain volumes in participants with ADHD than in controls. 2,3 Metaanalyses of regions of interest (ROI) studies have shown significantly smaller volume in total and right cerebral volume, frontal brain areas, the right caudate and cerebellar regions in participants with ADHD than in controls. 3 Volumetric ROI studies, however, are restricted to a small number of a priori selected regions, which could give rise to selection bias.A method that circumvents this potential bias and allows a whole brain, hypothesis-free analysis is voxel-based morphometry (VBM), 4 an MRI analysis technique that assesses differences between groups in voxelwise grey matter volume. Three meta-analyses of VBM studies reporting on partly the same samples have investigated the most prominent volumetric differences between participants with ADHD and controls. [5][6][7] The first meta-analysis (114 children with ADHD and 143 controls) reported smaller grey matter volume in the right putamen and globus pallidus in children with ADHD than in controls. 5 A more recent meta-analysis (202 children and adolescents and 176 adults with ADHD and 344 controls) confirmed the reduced localized subcortical grey matter findings Background: Data on structural brain alterations in patients with attention-deficit/hyperactivity disorder (ADHD) have been inconsistent. Both ADHD and brain volumes have a strong genetic loading, but whether brain alterations in patients with ADHD are familial has been underexplored. We aimed to detect structural brain alterations in adolescents and young adults with ADHD compared with healthy controls. We examined whether these alterations were also found in their unaffected siblings, using a uniquely large sample. Methods: We performed voxelbased morphometry analyses on MRI scans of patients with ADHD, their unaffected siblings and typically developing controls. We identified brain areas that differed between participants with ADHD and controls and investigated whether these areas were different in unaffected siblings. Influences of medication use, age, sex and IQ were considered. Results: Our sample included 307 patients with ADHD, 169 unaffected siblings and 196 typically developing controls (mean age 17.2 [range 8-30] yr). Compared with controls, participants with ADHD had significantly smaller grey matter volume in 5 clusters located in the precentral gyrus, medial and orbitofrontal cortex, and (para)cingulate cortices. Unaffected siblings showed intermediate volumes significantly different from controls in 4 of these clusters (all except the precentral gyrus). Medication use, age, sex and IQ did not have an undue influence on the results. Limitations: Our sample was heterogeneous, most participants with ADHD were taking medication, and the comparison was cross-sectional. Conclusion...

Shared genetic etiology between obsessive-compulsive disorder, obsessive-compulsive symptoms in the population, and insulin signaling

“…We first compiled a set of all genes encoding proteins within our molecular landscape of OCD (26) (see above). This resulted in a set of 51 autosomal genes for subsequent analyses.…”

“…In a study aiming to identify molecular mechanisms underlying OCD, we earlier performed integration of the top ranked-results from the existing GWASs. This resulted in a ‘molecular landscape’ that suggested the involvement of genes regulating postsynaptic dendritic spine formation and function through central nervous system (CNS) insulin-dependent signalling (26). Support for a role of dysregulated insulin signaling in OCD and OCS comes from studies showing increased OCS in men with type 1 diabetes (27) and from a study indicating that OCD patients have a higher risk of developing type 2 diabetes (T2D) (28).…”

Genome-wide analyses indirectly implicate miRNA regulatory mechanisms in Obsessive-compulsive Disorder psychopathology

“…Both CGNL1 and GPR109A were identified as potential regulatory targets associated with increased risk for OCD. CGNL1 is found at adherent and tight cell-cell junctions and coordinates junction assembly (Citi et al, 2012;Rees et al, 2014;van de Vondervoort et al, 2016). Little is known about the role of CGNL1 in human disease (Citi et al, 2012).…”

COMPULS: design of a multicenter phenotypic, cognitive, genetic, and magnetic resonance imaging study in children with compulsive syndromes

“…While glutamate has an important role in the neurobiology of compulsivity and impulsivity and the related disorders, it is certainly not the only biological substrate involved. For example, we have recently identified central insulin signalling as an additional molecular cascade involved in OCD [30] and neurite outgrowth as a neurodevelopmental process implicated in ADHD [31] and ASD [32]. Genetic variation in such genes is likely to alter their regulation and/or function, leading to changes in the encoded proteins and biological processes contributing to proper cell function.…”