The genetics of cortical organisation and development: a study of 2,347 neuroimaging phenotypes
The genetics of cortical organisation and development: a study of 2,347 neuroimaging phenotypes
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DOI：
10.1101/2022.09.08.507084
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发表时间：
2022-09
期刊：
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通讯作者：
V. Warrier;E. Stauffer;Q. Huang;E. Wigdor;E. Slob;J. Seidlitz;L. Ronan;S. Valk;T. Mallard;A. Grotzinger;R. Romero-García;S. Baron-Cohen;D. Geschwind;Madeline A. Lancaster;G. Murray;M. Gandal;A. Alexander-Bloch;H. Won;H. Martin;E. Bullmore;R. Bethlehem
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作者：
V. Warrier;E. Stauffer;Q. Huang;E. Wigdor;E. Slob;J. Seidlitz;L. Ronan;S. Valk;T. Mallard;A. Grotzinger;R. Romero-García;S. Baron-Cohen;D. Geschwind;Madeline A. Lancaster;G. Murray;M. Gandal;A. Alexander-Bloch;H. Won;H. Martin;E. Bullmore;R. Bethlehem
我们对人类大脑皮层的遗传结构的理解是有限的，无论是在大脑结构表型的多样性和它们与遗传变异的关联的解剖粒度。在这里，我们对13种结构和弥散磁共振成像衍生的皮质表型进行了全基因组关联荟萃分析，这些表型在全球范围内和来自英国生物银行和ABCD队列的36，843名个体的180个双侧平均区域进行了测量。这些表型包括皮质厚度、表面积、灰质体积、以及折叠、神经突密度和水扩散的测量。我们确定了4，349个与全球和区域表型相关的实验范围内的显著位点。多行分析确定了四个遗传潜在结构和表面积和皮质折叠的一些措施之间的因果关系。这些潜在的结构部分涉及不同的潜在基因表达轨迹在发展过程中，并为不同的细胞类型富集。我们还确定了神经发育和限制基因的差异富集，并证明了与表面积和体积相关的常见遗传变异与头部疾病相关。最后，我们确定了复杂的表型间和区域间的遗传关系，反映了它们之间的发育差异。这些分析有助于细化常见遗传变异在人类皮层发育和组织中的作用。一句话总结了2,347个神经影像表型的GWAS，揭示了大脑皮层的全球和区域遗传组织，潜在的细胞和发育过程，以及与神经发育和头部疾病的联系。
Our understanding of the genetic architecture of the human cerebral cortex is limited both in terms of the diversity of brain structural phenotypes and the anatomical granularity of their associations with genetic variants. Here, we conducted genome-wide association meta-analysis of 13 structural and diffusion magnetic resonance imaging derived cortical phenotypes, measured globally and at 180 bilaterally averaged regions in 36,843 individuals from the UK Biobank and the ABCD cohorts. These phenotypes include cortical thickness, surface area, grey matter volume, and measures of folding, neurite density, and water diffusion. We identified 4,349 experiment-wide significant loci associated with global and regional phenotypes. Multiple lines of analyses identified four genetic latent structures and causal relationships between surface area and some measures of cortical folding. These latent structures partly relate to different underlying gene expression trajectories during development and are enriched for different cell types. We also identified differential enrichment for neurodevelopmental and constrained genes and demonstrate that common genetic variants associated with surface area and volume specifically are associated with cephalic disorders. Finally, we identified complex inter-phenotype and inter-regional genetic relationships among the 13 phenotypes which reflect developmental differences among them. These analyses help refine the role of common genetic variants in human cortical development and organisation. One sentence summary GWAS of 2,347 neuroimaging phenotypes shed light on the global and regional genetic organisation of the cortex, underlying cellular and developmental processes, and links to neurodevelopmental and cephalic disorders.