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Imaging Genetics Center, Institute for Neuroimaging &Informatics, Keck School of Medicine of the University of Southern California, Los Angeles, California 90292, USA.
1] Imaging Genetics Center, Institute for Neuroimaging &Informatics, Keck School of Medicine of the University of Southern California, Los Angeles, California 90292, USA. [2] Neurogenetics Program, Department of Neurology, UCLA School of Medicine, Los Angeles, California 90095, USA.
Nature. 2015 Apr 9;520(7546):224-9. doi: 10.1038/nature14101. Epub 2015 Jan 21.
The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.
人类大脑高度复杂的结构在很大程度上受基因影响。大脑皮层下区域与皮层区域形成回路，以协调运动、学习、记忆和动机，而回路改变会导致异常行为和疾病。为了研究常见基因变异如何影响这些脑区的结构，我们对来自50个队列的30717名个体的磁共振图像所衍生的七个皮层下区域的体积和颅内体积进行了全基因组关联研究。我们鉴定出五个影响壳核和尾状核体积的新基因变异。我们还发现了三个对海马体体积和颅内体积有先前已确定影响的基因座的更强证据。这些变异对脑结构显示出特定的体积效应，而非对整个结构的全局效应。在壳核中发现了最强的效应，一个对体积有可重复影响的新基因间位点（rs945270；P = 1.08×10⁻³³；可解释0.52%的方差）显示出在脑和血液组织中改变KTN1基因表达的证据。影响壳核体积的变异聚集在调节细胞凋亡、轴突导向和囊泡运输的发育基因附近。这些基因变异的鉴定为深入了解人类大脑发育变异的原因提供了线索，并可能有助于确定神经精神功能障碍的机制。
