Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA.
Department of Mental Health, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA.
Mol Psychiatry. 2020 Aug;25(8):1822-1834. doi: 10.1038/s41380-018-0078-5. Epub 2018 Jun 13.
The 22q11.2 deletion (22q11DS) is a common chromosomal microdeletion and a potent risk factor for psychotic illness. Prior studies reported widespread cortical changes in 22q11DS, but were generally underpowered to characterize neuroanatomic abnormalities associated with psychosis in 22q11DS, and/or neuroanatomic effects of variability in deletion size. To address these issues, we developed the ENIGMA (Enhancing Neuro Imaging Genetics Through Meta-Analysis) 22q11.2 Working Group, representing the largest analysis of brain structural alterations in 22q11DS to date. The imaging data were collected from 10 centers worldwide, including 474 subjects with 22q11DS (age = 18.2 ± 8.6; 46.9% female) and 315 typically developing, matched controls (age = 18.0 ± 9.2; 45.9% female). Compared to controls, 22q11DS individuals showed thicker cortical gray matter overall (left/right hemispheres: Cohen's d = 0.61/0.65), but focal thickness reduction in temporal and cingulate cortex. Cortical surface area (SA), however, showed pervasive reductions in 22q11DS (left/right hemispheres: d = -1.01/-1.02). 22q11DS cases vs. controls were classified with 93.8% accuracy based on these neuroanatomic patterns. Comparison of 22q11DS-psychosis to idiopathic schizophrenia (ENIGMA-Schizophrenia Working Group) revealed significant convergence of affected brain regions, particularly in fronto-temporal cortex. Finally, cortical SA was significantly greater in 22q11DS cases with smaller 1.5 Mb deletions, relative to those with typical 3 Mb deletions. We found a robust neuroanatomic signature of 22q11DS, and the first evidence that deletion size impacts brain structure. Psychotic illness in this highly penetrant deletion was associated with similar neuroanatomic abnormalities to idiopathic schizophrenia. These consistent cross-site findings highlight the homogeneity of this single genetic etiology, and support the suitability of 22q11DS as a biological model of schizophrenia.
22q11.2 缺失（22q11DS）是一种常见的染色体微缺失，也是精神疾病的一个强有力的风险因素。先前的研究报告了 22q11DS 患者广泛的皮质变化，但普遍没有足够的能力来描述 22q11DS 与精神疾病相关的神经解剖异常，以及/或缺失大小的变异性的神经解剖影响。为了解决这些问题，我们成立了 ENIGMA（通过荟萃分析增强神经影像学遗传学）22q11.2 工作组，这是迄今为止对 22q11DS 大脑结构改变进行的最大分析。该成像数据来自全球 10 个中心，包括 474 名 22q11DS 患者（年龄=18.2±8.6；46.9%为女性）和 315 名典型发育的匹配对照者（年龄=18.0±9.2；45.9%为女性）。与对照组相比，22q11DS 个体的皮质灰质整体增厚（左侧/右侧半球：Cohen's d=0.61/0.65），但颞叶和扣带回皮质的厚度变薄。然而，皮质表面积（SA）在 22q11DS 中普遍减少（左侧/右侧半球：d=-1.01/-1.02）。基于这些神经解剖模式，22q11DS 病例与对照组的分类准确率为 93.8%。将 22q11DS-精神病与特发性精神分裂症（ENIGMA-精神分裂症工作组）进行比较，发现受影响的大脑区域存在显著的趋同，特别是在前额颞叶皮层。最后，与具有典型 3Mb 缺失的患者相比，较小的 1.5Mb 缺失的 22q11DS 患者的皮质 SA 显著更大。我们发现了 22q11DS 的一个强大的神经解剖特征，以及缺失大小影响大脑结构的第一个证据。在这个高外显率缺失中，精神病与特发性精神分裂症的神经解剖异常相似。这些一致的跨站点发现强调了单一遗传病因的同质性，并支持 22q11DS 作为精神分裂症的生物学模型的适用性。
