Stanley Center for Psychiatric Genetics.
Department of Psychiatry.
J Psychopathol Clin Sci. 2022 Aug;131(6):674-688. doi: 10.1037/abn0000765. Epub 2022 Jun 23.
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 highlight the potentially dynamic nature of schizophrenia genetic effects across the lifespan and emphasize the utility of integrating neuroimaging methods with developmental behavior genetic approaches to elucidate the nature and timing of risk-conferring processes in psychopathology. (PsycInfo Database Record (c) 2022 APA, all rights reserved).
精神分裂症的发病风险在成年早期达到高峰，这是大脑发育的关键时期。尽管已经提出了几个有影响力的理论模型来解释大脑病理与临床发病之间的发展关系，但据我们所知，尚无研究直接评估这些模型对精神分裂症发育遗传效应与大脑结构之间关系的预测。为了解决这个问题，我们引入了一个框架来估计精神分裂症遗传变异对大脑结构表型的影响，该影响贯穿整个生命周期。共有 506 名参与者，包括 30 名精神分裂症患者、来自 32 个至少有 2 名一级精神分裂症亲属的家庭的 200 名亲属（年龄在 12-85 岁之间）以及 276 名无关对照者，他们接受了 MRI 检查以评估区域性皮质厚度（CT）和皮质表面积（CSA）。进行遗传方差分解分析以区分在精神分裂症发病风险高峰年龄之前（即早期神经发育效应）、在发病风险高峰年龄之后（晚期神经发育效应）和在发病风险后期平台期间（神经退行性效应）精神分裂症神经遗传效应的最显著特征。精神分裂症与皮质特征之间的遗传相关性表明，额极和脑岛 CSA 具有早期神经发育效应，整体 CSA 和额极、顶极和枕极 CSA 具有晚期神经发育效应，颞极 CT 和顶极 CSA 可能具有神经退行性效应。重要的是，这些发育神经遗传效应是精神分裂症特有的，而不是非精神病性抑郁症所具有的。我们的研究结果强调了精神分裂症遗传效应在整个生命周期中潜在的动态性质，并强调了将神经影像学方法与发育行为遗传学方法相结合以阐明精神病理学中风险赋予过程的性质和时间的实用性。（PsycInfo 数据库记录（c）2022 APA，保留所有权利）。
