Age-dependent effects of schizophrenia genetic risk on cortical thickness and cortical surface area: Evaluating evidence for neurodevelopmental and neurodegenerative models of schizophrenia.

Abstract

Risk for schizophrenia peaks during early adulthood, a critical period for brain development. Although several influential theoretical models have been proposed for the developmental relationship between brain pathology and clinical onset, to our knowledge, no study has directly evaluated the predictions of these models for schizophrenia developmental genetic effects on brain structure. To address this question, we introduce a framework to estimate the effects of schizophrenia genetic variation on brain structure phenotypes across the life span. Five-hundred and six participants, including 30 schizophrenia probands, 200 of their relatives (aged 12-85 years) from 32 families with at least two first-degree schizophrenia relatives, and 276 unrelated controls, underwent MRI to assess regional cortical thickness (CT) and cortical surface area (CSA). Genetic variance decomposition analyses were conducted to distinguish among schizophrenia neurogenetic effects that are most salient before schizophrenia peak age-of-risk (i.e., early neurodevelopmental effects), after peak age-of-risk (late neurodevelopmental effects), and during the later plateau of age-of-risk (neurodegenerative effects). Genetic correlations between schizophrenia and cortical traits suggested early neurodevelopmental effects for frontal and insula CSA, late neurodevelopmental effects for overall CSA and frontal, parietal, and occipital CSA, and possible neurodegenerative effects for temporal CT and parietal CSA. Importantly, these developmental neurogenetic effects were specific to schizophrenia and not found with nonpsychotic depression. Our findings

Gene Expressions Preferentially Influence Cortical Thickness of Human Connectome Project Atlas Parcellated Regions in First-Episode Antipsychotic-Naïve Psychoses

“…In our previous study, we observed that CT and SA showed significant neurogenetic effects in the later phases of illness but not in the early phases. 54 We also observed that the genetic effects shared between deficits in general cognition and schizophrenia were nonsignificant in the early phases of the illness than during the later stages. 55 These data suggest that gene expression differences may impact CT changes in patients with longer duration of illness than those with short duration of illness.…”

The Risk for Schizophrenia–Bipolar Spectrum: Does the Apple Fall Close to the Tree? A Narrative Review

“…Particularly, the ENIGMA Relatives Working Group reported a reduction in mean cortical thickness (CT) in SCZ-RELs compared to HCs [92]. Additionally, a study conducted on 200 SCZ-RELs (aged 12-85 years) and 276 unrelated controls suggested early neurodevelopmental effects of the SCZ genetic risk for frontal and insular SA, late neurodevelopmental effects for overall cortical SA, and frontal, parietal, and occipital SA, and possible neurodegenerative effects for temporal CT and parietal SA [97]. Interestingly, a reduction in frontal and temporal SA in SCZ-RELs was correlated with subjective cognitive dysfunction and predisposition to hallucinations [98].…”