Objective:

Autism spectrum disorder (ASD) is accompanied by highly individualized neuroanatomical deviations that potentially map onto distinct genotypes and clinical phenotypes. This study aimed to link differences in brain anatomy to specific biological pathways to pave the way toward targeted therapeutic interventions.

Methods:

The authors examined neurodevelopmental differences in cortical thickness and their genomic underpinnings in a large and clinically diverse sample of 360 individuals with ASD and 279 typically developing control subjects (ages 6–30 years) within the EU-AIMS Longitudinal European Autism Project (LEAP). The authors also examined neurodevelopmental differences and their potential pathophysiological mechanisms between clinical ASD subgroups that differed in the severity and pattern of sensory features.

Results:

In addition to significant between-group differences in “core” ASD brain regions (i.e., fronto-temporal and cingulate regions), individuals with ASD manifested as neuroanatomical outliers within the neurotypical cortical thickness range in a wider neural system, which was enriched for genes known to be implicated in ASD on the genetic and/or transcriptomic level. Within these regions, the individuals’ total (i.e., accumulated) degree of neuroanatomical atypicality was significantly correlated with higher polygenic scores for ASD and other psychiatric conditions, and it scaled with measures of symptom severity. Differences in cortical thickness deviations were also associated with distinct sensory subgroups, especially in brain regions expressing genes involved in excitatory rather than inhibitory neurotransmission.

Conclusions:

The study findings corroborate the link between macroscopic differences in brain anatomy and the molecular mechanisms underpinning heterogeneity in ASD, and provide future targets for stratification and subtyping.

中文翻译：

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自闭症谱系障碍中皮质厚度的个体差异及其基因组基础

客观的：

自闭症谱系障碍 (ASD) 伴随着高度个体化的神经解剖学偏差，这些偏差可能映射到不同的基因型和临床表型。这项研究旨在将大脑解剖学的差异与特定的生物学途径联系起来，为有针对性的治疗干预铺平道路。

方法：

作者在 EU-AIMS 纵向欧洲自闭症项目 (LEAP) 中检查了 360 名 ASD 患者和 279 名正常发育的对照受试者（年龄 6-30 岁）的大量临床多样化样本中皮质厚度的神经发育差异及其基因组基础。作者还检查了感觉特征的严重程度和模式不同的临床 ASD 亚组之间的神经发育差异及其潜在的病理生理机制。

结果：

除了“核心”ASD大脑区域（即额颞叶和扣带回区域）的显着组间差异外，患有ASD的个体在更广泛的神经系统中表现为神经典型皮层厚度范围内的神经解剖异常值，该神经系统富含基因已知在遗传和/或转录组水平上与 ASD 有关。在这些区域内，个体的总（即累积）神经解剖异常程度与 ASD 和其他精神疾病的较高多基因评分显着相关，并且与症状严重程度的测量值成比例。皮质厚度偏差的差异也与不同的感觉亚组有关，特别是在表达与兴奋性而非抑制性神经传递有关的基因的大脑区域中。

结论：

研究结果证实了大脑解剖学的宏观差异与支持 ASD 异质性的分子机制之间的联系，并为分层和亚型分类提供了未来的目标。