Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada.
Bloorview Research Institute, Toronto, Ontario, Canada.
JAMA Psychiatry. 2020 Nov 1;77(11):1127-1136. doi: 10.1001/jamapsychiatry.2020.1495.
Many psychiatric disorders can be conceptualized as disorders of brain maturation during childhood and adolescence. Discovering the neurobiological underpinnings of brain maturation may elucidate molecular pathways of vulnerability and resilience to such disorders.
To investigate the underlying neurobiological mechanisms of age-associated cortical thinning during maturation and their implications for psychiatric disorders.
DESIGN, SETTING, AND PARTICIPANTS: This multicohort analysis used data from 3 community-based studies. The Saguenay Youth Study provided data from 1024 adolescents who were recruited at a single site in Quebec, Canada. The IMAGEN cohort provided data from 1823 participants who were recruited in 8 European cities. The Brazil High Risk Cohort Study for the Development of Childhood Psychiatric Disorders provided data from 815 participants who were recruited in 2 Brazilian cities. Cortical thickness was estimated from the results of magnetic resonance imaging (MRI) scans, and age-associated cortical thinning was estimated in 34 cortical regions. Gene expression from the Allen Human Brain Atlas was aligned with the same regions. Similarities in the interregional profiles of gene expression and the profiles of age-associated cortical thinning were measured. The involvement of dendrites, dendritic spines, and myelin was tested using 3 gene panels. Enrichment for genes associated with psychiatric disorders was tested among the genes associated with thinning and their coexpression networks. Data analysis was conducted between March and October 2019.
MRI-derived estimates of age-associated cortical thinning and gene expression in 34 cortical regions.
A total of 3596 individuals aged 9 to 21 years were included in this study. Of those, 1803 participants (50.1%) were female, and the mean (SD) age was 15.2 (2.6) years. Interregional profiles of age-associated cortical thinning were associated with interregional gradients in the expression of genes associated with dendrites, dendritic spines, and myelin; the variance in thinning explained by the gene panels across different points ranged from 0.45% to 10.55% for the dendrite panel, 0.00% to 9.98% for the spine panel, and 0.19% to 26.39% for the myelin panel. These genes and their coexpression networks were enriched for genes associated with several psychiatric disorders.
In this study, genetic similarity between interregional variation in cortical thinning during maturation and multiple psychiatric disorders suggests overlapping molecular underpinnings. This finding adds to the understanding of the neurodevelopmental mechanisms of psychiatric disorders.
许多精神疾病可以被概念化为儿童和青少年时期大脑成熟过程中的障碍。发现大脑成熟的神经生物学基础可以阐明易患此类疾病的分子途径和恢复能力。
研究与年龄相关的皮质变薄在成熟过程中的潜在神经生物学机制及其对精神疾病的影响。
设计、地点和参与者：这项多队列分析使用了来自 3 项基于社区的研究的数据。萨格奈青年研究提供了来自加拿大魁北克一个地点招募的 1024 名青少年的数据。IMAGEN 队列提供了来自 8 个欧洲城市招募的 1823 名参与者的数据。巴西儿童期精神疾病发展高危队列研究提供了来自巴西两个城市招募的 815 名参与者的数据。从磁共振成像 (MRI) 扫描结果中估计皮质厚度，并在 34 个皮质区域估计与年龄相关的皮质变薄。从艾伦人类大脑图谱获得的基因表达与相同区域对齐。测量基因表达和与年龄相关的皮质变薄的区域间分布的相似性。使用 3 个基因谱测试树突、树突棘和髓鞘的参与。在与变薄相关的基因及其共表达网络中，测试与精神疾病相关的基因的富集情况。数据分析于 2019 年 3 月至 10 月进行。
MRI 衍生的与 34 个皮质区域的年龄相关皮质变薄和基因表达的估计。
这项研究共纳入 3596 名 9 至 21 岁的个体。其中 1803 名参与者 (50.1%) 为女性，平均 (SD) 年龄为 15.2(2.6)岁。与年龄相关的皮质变薄的区域间分布与与树突、树突棘和髓鞘相关基因的表达的区域间梯度相关；在不同点，由基因图谱解释的变薄方差范围从树突图谱的 0.45%到 10.55%，棘图谱的 0.00%到 9.98%，髓鞘图谱的 0.19%到 26.39%。这些基因及其共表达网络在与多种精神疾病相关的基因中富集。
在这项研究中，成熟过程中皮质变薄的区域间变化与多种精神疾病的遗传相似性表明存在重叠的分子基础。这一发现增加了对精神疾病神经发育机制的理解。
