Gene network effects on brain microstructure and intellectual performance identified in 472 twins.
Gene network effects on brain microstructure and intellectual performance identified in 472 twins.
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DOI：
10.1523/jneurosci.5993-11.2012
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发表时间：
2012-06-20
期刊：
影响因子：
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通讯作者：
Thompson PM
中科院分区：
文献类型：
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作者：
Chiang MC;Barysheva M;McMahon KL;de Zubicaray GI;Johnson K;Montgomery GW;Martin NG;Toga AW;Wright MJ;Shapshak P;Thompson PM
神经科学的一个主要挑战是发现哪些基因影响大脑的完整性、连通性和智力功能。发现有影响力的基因为神经科学带来了巨大的希望，但典型的全基因组搜索会逐一评估大约一百万个基因变异，导致难以处理的假阳性率，即使是在大量的受试者样本中。更棘手的问题是哪些基因相互作用，以及它们如何共同影响大脑的连通性。在这里，我们报告了一种新的方法，发现哪些基因在大脑扫描的所有对点上对大脑线路和纤维完整性有贡献。我们研究了来自472对双胞胎及其非双胞胎兄弟姐妹（平均年龄：23.7±2.1 SD年；193 M/279 F）的人脑图像中数千个点的遗传相关性。我们将聚类与全基因组扫描结合起来，寻找具有共同遗传决定的大脑系统。然后，我们以一种新的方式过滤图像，以增强发现因果基因的能力。通过网络分析，我们发现了一个影响健康年轻人大脑线路的基因网络。我们的新策略使得发现影响大脑完整性的基因在计算上更加容易。基因网络表现出小世界和无标度的拓扑结构，表明基因相互作用的效率，以及对网络中断的弹性。网络中心的遗传变异通过调节表现智商（IQ）与主要白质束（如胼胝体和脾、扣带、视神经辐射和上纵束）完整性之间的关联来影响智力表现。
A major challenge in neuroscience is finding which genes affect brain integrity, connectivity, and intellectual function. Discovering influential genes holds vast promise for neuroscience, but typical genome-wide searches assess around one million genetic variants one-by-one, leading to intractable false positive rates, even with vast samples of subjects. Even more intractable is the question of which genes interact and how they work together to affect brain connectivity. Here we report a novel approach that discovers which genes contribute to brain wiring and fiber integrity at all pairs of points in a brain scan. We studied genetic correlations between thousands of points in human brain images from 472 twins and their non-twin siblings (mean age: 23.7±2.1 SD years; 193 M/279 F). We combined clustering with genome-wide scanning to find brain systems with common genetic determination. We then filtered the image in a new way to boost power to find causal genes. Using network analysis, we found a network of genes that affect brain wiring in healthy young adults. Our new strategy makes it more computationally tractable to discover genes that affect brain integrity. The gene network showed small-world and scale-free topologies, suggesting efficiency in genetic interactions, and resilience to network disruption. Genetic variants at hubs of the network influence intellectual performance by modulating associations between performance intelligence quotient (IQ) and the integrity of major white matter tracts, such as the callosal genu and splenium, cingulum, optic radiations, and the superior longitudinal fasciculus.