Genome-wide Identification of Variants Affecting Early Human Brain Development

描述（由申请人提供）：最近的研究强烈表明，精神和神经发育障碍（包括自闭症、智力残疾、注意力缺陷障碍和精神分裂症）的风险存在共同的、由遗传决定的途径，但没有研究调查遗传变异与首次发现临床症状的年龄之前的人类大脑发育之间的关系。当前应用的主要目标是使用基因组学的尖端技术来识别影响出生后早期大脑发育的常见和罕见遗传变异，这是一个非常动态的时间，可能是神经发育障碍病因学的关键。颅内容积（ICV）、总白质、总灰质、侧脑室容积和白质束的成熟在新生儿中是遗传的。该项目将测试几种主要的遗传机制，以解释这种高遗传性。(1)我们将测试大脑结构表型的变异是否可以通过中等到大效应大小的常见变异来预测，方法是在一个大的（900名受试者）和特征明确的儿童群体样本中对大约100万个单核苷酸多态性（snp）和全基因组拷贝数变异（CNV）探针进行基因分型，并在2周龄时使用T1加权、t2加权和扩散张量成像序列对大脑进行高分辨率MRI评估。分析将分两个阶段完成，一个是对先前与大脑发育有关的一组确定的遗传变异进行假设驱动测试，另一个是对基因组进行产生假设的无偏搜索，以确定先前未被怀疑的影响大脑发育的变异。(2)使用相同的数据集，我们将通过通路分析和先进的多标记关联模型，测试大脑结构表型的变异是否可以通过许多常见变异的综合效应来预测，每个变异的效应都很小。(3)我们还将使用该数据集来测试罕见基因CNVs的总负担是否预测大脑结构的变化。(4)我们将通过对20名脑室增大的儿童进行全外显子组测序来测试罕见的snp和/或小的插入和缺失是否与大脑发育有关，脑室增大是一种与神经发育障碍高度相关的表型。虽然这项资助的重点是新生儿期，但作为已经资助的研究的一部分，参与者也将在1岁、2岁、4岁和6岁时返回进行后续扫描和详细的发育评估。因此，最终，这项资助产生的信息可用于研究婴儿和幼儿期关键过渡时期大脑结构和功能发育轨迹的遗传决定因素。这是一个前所未有的机会，可以识别影响大脑发育的基因变异，潜在地介导精神和神经发育障碍的风险。更好地了解这种遗传机制有可能激发出迫切需要的预防、诊断和治疗的新方法。

DESCRIPTION (provided by applicant): Recent studies strongly suggest that there are common, genetically determined pathways to risk for psychiatric and neurodevelopmental disorders including autism, intellectual disability, attention deficit disorder, and schizophrenia, but no study has investigated the relationship between genetic variation and human brain development prior to the age at which clinical symptoms are first recognized. The primary objective of the current application is to use cutting-edge techniques in genomics to identify common and rare genetic variants which impact brain development in the early postnatal period, an extremely dynamic time which may be critical in the etiology of neurodevelopmental disorders. Intracranial volume (ICV), total white matter, total gray matter, lateral ventricle volume, and maturation of white matter tracts are heritable in neonates. The proposed project will test several major genetic mechanisms which could explain this high heritability. (1) We will test whether variation in structural brain phenotypes is predicted by common variants of moderate to large effect size by genotyping approximately 1 million single nucleotide polymorphisms (SNPs) and a genome-wide set of copy number variation (CNV) probes in a large (900 subject) and well-characterized population sample of children assessed with high-resolution MRI of the brain at 2 weeks of age with T1- weighted, T2-weighted, and diffusion tensor imaging sequences. Analysis will be completed in 2 stages, a hypothesis driven test of a defined set of genetic variants previously implicated in brain development and a hypothesis-generating unbiased search of the genome to identify previously unsuspected variants affecting brain development. (2) Using the same data set we will test whether variation in structural brain phenotypes is predicted by the combined effects of many common variants each with a small effect size through pathway analysis and advanced multi-marker association models. (3) We will also use this data set to test if the total burden of rare genic CNVs predicts variation in brain structure. (4) We will test whether rare SNPs and/or small insertions and deletions are associated with brain development by performing full exome sequencing in a subgroup of 20 children with enlarged ventricles, a phenotype which is highly relevant to neurodevelopmental disorders. While the focus of this grant is on the neonatal period, participants are also returning for follow-up scans and detailed developmental assessments at 1, 2, 4 and 6 yrs of age as part of 2 already funded studies. Thus, ultimately, the information generated in this grant can be used to study genetic determinates of the trajectories of structural and functional brain development across the critical transitional period of infancy and early childhood. This is an unprecedented opportunity to identify genetic variants which impact brain development, potentially mediating risk for psychiatric and neurodevelopmental disorders. A better understanding of such genetic mechanisms has the potential to inspire new approaches to prevention, diagnosis, and treatment which are urgently needed.