NORMENT, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
Transl Psychiatry. 2021 Mar 22;11(1):182. doi: 10.1038/s41398-021-01213-0.
Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.
低频 1q21.1 远端缺失和重复拷贝数变异（CNV）携带者易患多种神经发育障碍，包括精神分裂症、自闭症和智力障碍。人类携带者在缺失和重复携带者中分别显示出小头畸形和大头畸形的高发率。潜在的大脑结构多样性在很大程度上仍然未知。我们系统地在 ENIGMA-CNV 合作组织和英国生物银行的 38 个队列中调用 CNV，并鉴定了 28 个 1q21.1 远端缺失和 22 个重复携带者以及 37088 个非携带者（48%为男性），这些携带者来自 15 个不同的磁共振成像扫描仪站点。我们使用标准化方法比较了亚皮质和皮质脑测量值（全部）和认知表现（仅英国生物银行）在携带者组之间，还测试了大脑结构对认知的中介作用。我们发现拷贝数对颅内体积（ICV）和总皮质表面积的正剂量效应，在额皮质和扣带回皮质中影响最大，对尾状核和海马体积的负剂量效应。携带者在英国生物银行的认知任务中表现出明显的认知缺陷特征，在重复携带者中认知缺陷程度中等，在缺失携带者中认知缺陷程度较大——后者可能由 ICV 或皮质表面积介导。这些结果通过证明特定脑结构上的基因剂量效应和对认知功能的影响，为神经发育障碍的病理生物学机制提供了启示。
