Polygenic risk for obsessive-compulsive disorder (OCD) predicts brain response during working memory task in OCD, unaffected relatives, and healthy controls

Abstract

Alterations in frontal and parietal neural activations during working memory task performance have been suggested as a candidate endophenotype of obsessive-compulsive disorder (OCD) in studies involving first-degree relatives. However, the direct link between genetic risk for OCD and neuro-functional alterations during working memory performance has not been investigated to date. Thus, the aim of the current functional magnetic resonance imaging (fMRI) study was to test the direct association between polygenic risk for OCD and neural activity during the performance of a numeric n-back task with four working memory load conditions in 128 participants, including patients with OCD, unaffected first-degree relatives of OCD patients, and healthy controls. Behavioral results show a significant performance deficit at high working memory load in both patients with OCD and first-degree relatives (p < 0.05). A whole-brain analysis of the fMRI data indicated decreased neural activity in bilateral inferior parietal lobule and dorsolateral prefrontal cortex in both patients and relatives. Most importantly, OCD polygenic risk scores predicted neural activity in orbitofrontal cortex. Results indicate that genetic risk for OCD can partly explain alterations in brain response during working memory performance, supporting the notion of a neuro-functional endophenotype for OCD.

Opening new vistas on obsessive-compulsive disorder with the observing response task

“…Multiple studies have observed memory changes in OCD patients. Working memory deficits have been observed in OCD patients across a range of behavioural tests, including the canonical N-back task (Nakao et al, 2009 ; de Vries et al, 2014 ; Heinzel et al, 2021 ), the impaired performance of which was associated with increased activation of frontal brain regions. This included increased activity in the right dorsolateral prefrontal cortex (Nakao et al, 2009 ) and aberrant frontoparietal activation (de Vries et al, 2014 ).…”

Link Between Obsessive-Compulsive Disorder and ApoE Gene Polymorphisms

“… 17 Many neuropsychological and imaging studies have showed the poor and slack performance of OCD patients on executive function tasks. 18 , 19 However, few studies have been performed on early- and late-onset OCD. Contrary to expectations, in the study of Segalas et al, tests evaluating executive functioning, visual memory, and verbal memory in late-onset OCD yielded worse results when compared with those of early-onset OCD.…”

SAPAP3, SPRED2, and obsessive-compulsive disorder: the search for fundamental phenotypes

“…Among these, cognitive endophenotypes have been the most frequently documented (Vaghi, 2021 ) and have been observed even in pediatric OCD (Abramovitch et al, 2021 ). Recent evidence suggests that the polygenic risk score, a measure of genetic vulnerability toward OCD, is significantly correlated with alterations in brain activity during the performance of cognitive tasks not just in patients with OCD and their unaffected relatives, but in healthy controls (Heinzel et al, 2021 ). This result suggests the possibility of a “continuum” of genetic vulnerability to OCD that could cause subtle deficits in higher-order cognitive functions, most probably through alterations in brain development and functional connectivity.…”