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，存在常见的、由基因决定的精神和神经发育障碍的风险途径，包括自闭症、智力残疾、注意力缺陷障碍和精神分裂症，但在首次发现临床症状的年龄之前，没有研究调查基因变异与人类大脑发育之间的关系。目前应用的主要目标是利用基因组学的尖端技术来识别在出生后早期影响大脑发育的常见和罕见的遗传变异，这是一个极其动态的时间，可能在神经发育障碍的病因学中起关键作用。新生儿的颅内体积(ICV)、总白质、总灰质、侧脑室体积和白质束成熟是可遗传的。这项拟议的项目将测试几种主要的遗传机制，这些机制可以解释这种高遗传性。(1)我们将通过对大约100万个单核苷酸多态(SNPs)和一组全基因组的拷贝数变异(CNV)探针进行基因分型，测试是否可以通过中到大效应大小的常见变异来预测大脑结构表型的变异。在两周大的儿童人群样本中，我们使用T1加权、T2加权和扩散张量成像序列对高分辨率脑MRI进行评估。分析将分两个阶段完成，对先前与大脑发育有关的一组已定义的遗传变异进行假设驱动测试，并对基因组进行假设生成的无偏搜索，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来检验脑结构表型的变异是否由许多共同的变量和先进的多标记关联模型来预测，每个变量的影响大小都很小。(3)我们还将使用这个数据集来测试稀有基因CNV的总负担是否可以预测大脑结构的变化。(4)我们将通过对20名脑室扩大的儿童进行全外显子组测序，测试罕见的SNPs和/或微小的插入和缺失是否与大脑发育有关。脑室扩大是一种与神经发育障碍高度相关的表型。虽然这笔赠款的重点是新生儿期，但参与者也会在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，这是已经资助的两项研究的一部分。因此，最终，这笔赠款中产生的信息可以用于研究婴儿和儿童早期关键过渡时期大脑结构和功能发育轨迹的基因决定因素。这是一个史无前例的机会，可以识别影响大脑发育的基因变异，潜在地调节精神和神经发育障碍的风险。对这种遗传机制的更好理解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.