Bhatt Ravi R, Gadewar Shruti P, Shetty Ankush, Ba Gari Iyad, Haddad Elizabeth, Javid Shayan, Ramesh Abhinaav, Nourollahimoghadam Elnaz, Zhu Alyssa H, de Leeuw Christiaan, Thompson Paul M, Medland Sarah E, Jahanshad Neda
Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey, CA, USA.
Department of Complex Trait Genetics, Centre for Neurogenomics and Cognitive Research, VU University, Amsterdam, The Netherlands.
bioRxiv. 2024 Jul 26:2024.07.22.603147. doi: 10.1101/2024.07.22.603147.
The corpus callosum (CC) is the largest set of white matter fibers connecting the two hemispheres of the brain. In humans, it is essential for coordinating sensorimotor responses, performing associative/executive functions, and representing information in multiple dimensions. Understanding which genetic variants underpin corpus callosum morphometry, and their shared influence on cortical structure and susceptibility to neuropsychiatric disorders, can provide molecular insights into the CC's role in mediating cortical development and its contribution to neuropsychiatric disease. To characterize the morphometry of the midsagittal corpus callosum, we developed a publicly available artificial intelligence based tool to extract, parcellate, and calculate its total and regional area and thickness. Using the UK Biobank (UKB) and the Adolescent Brain Cognitive Development study (ABCD), we extracted measures of midsagittal corpus callosum morphometry and performed a genome-wide association study (GWAS) meta-analysis of European participants (combined = 46,685). We then examined evidence for generalization to the non-European participants of the UKB and ABCD cohorts (combined = 7,040). Post-GWAS analyses implicate prenatal intracellular organization and cell growth patterns, and high heritability in regions of open chromatin, suggesting transcriptional activity regulation in early development. Results suggest programmed cell death mediated by the immune system drives the thinning of the posterior body and isthmus. Global and local genetic overlap, along with causal genetic liability, between the corpus callosum, cerebral cortex, and neuropsychiatric disorders such as attention-deficit/hyperactivity and bipolar disorders were identified. These results provide insight into variability of corpus callosum development, its genetic influence on the cerebral cortex, and biological mechanisms related to neuropsychiatric dysfunction.
胼胝体（CC）是连接大脑两个半球的最大白质纤维束。在人类中，它对于协调感觉运动反应、执行联想/执行功能以及在多个维度上呈现信息至关重要。了解哪些基因变异构成胼胝体形态测量的基础，以及它们对皮质结构和神经精神疾病易感性的共同影响，可以为胼胝体在介导皮质发育中的作用及其对神经精神疾病的贡献提供分子层面的见解。为了表征正中矢状面胼胝体的形态，我们开发了一种基于人工智能的公开可用工具，用于提取、分割并计算其总面积和区域面积以及厚度。利用英国生物银行（UKB）和青少年大脑认知发展研究（ABCD），我们提取了正中矢状面胼胝体形态测量指标，并对欧洲参与者进行了全基因组关联研究（GWAS）荟萃分析（合并样本量 = 46,685）。然后，我们检验了将研究结果推广到UKB和ABCD队列中的非欧洲参与者的证据（合并样本量 = 7,040）。GWAS后分析表明，产前细胞内组织和细胞生长模式以及开放染色质区域的高遗传性，提示早期发育中的转录活性调节。结果表明，免疫系统介导的程序性细胞死亡导致胼胝体后体和峡部变薄。我们确定了胼胝体、大脑皮质与注意力缺陷多动障碍和双相情感障碍等神经精神疾病之间的全局和局部遗传重叠以及因果遗传易感性。这些结果为胼胝体发育的变异性、其对大脑皮质的遗传影响以及与神经精神功能障碍相关的生物学机制提供了见解。
