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，存在常见的遗传决定的精神和神经发育障碍风险途径，包括自闭症，智力残疾，注意力缺陷障碍和精神分裂症，但没有研究调查遗传变异与首次识别临床症状的年龄之前的人类大脑发育之间的关系。本申请的主要目的是使用基因组学中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的病因学关键。新生儿颅内体积（ICV）、总白色物质、总灰质、侧脑室体积和白色物质束的成熟度是可遗传的。拟议的项目将测试几个主要的遗传机制，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性（SNP）和一组全基因组拷贝数变异（CNV）探针进行基因分型，在一个大样本中测试结构脑表型的变异是否可以通过中到大效应量的常见变异来预测。（900名受试者）和充分表征的儿童群体样本，在2周龄时使用T1加权的高分辨率脑部MRI进行评估，T2加权和扩散张量成像序列。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定义的遗传变异进行假设驱动检验，另一个是对基因组进行假设生成无偏搜索，以识别影响大脑发育的先前未被怀疑的变异。(2)使用相同的数据集，我们将测试结构脑表型的变化是否通过许多常见变体的组合效应来预测，每个变体通过通路分析和高级多标记关联模型具有较小的效应量。(3)我们还将使用该数据集来测试罕见基因CNVs的总负荷是否预测大脑结构的变化。(4)我们将测试是否罕见的SNP和/或小的插入和缺失与大脑发育相关，通过在20名脑室扩大儿童的亚组中进行全外显子组测序，这是一种与神经发育障碍高度相关的表型。虽然这项赠款的重点是新生儿期，但参与者也将在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，作为2项已资助研究的一部分。因此，最终，在这个补助金中产生的信息可以用来研究在婴儿期和幼儿期的关键过渡期的结构和功能大脑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遗传变异，可能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新的方法来预防，诊断和治疗是迫切需要的。 公共卫生相关性：本申请的主要目标是鉴定预测人类早期脑发育的常见和罕见遗传变体;这一时期在精神和神经发育障碍如自闭症、精神分裂症、智力残疾和注意力缺陷障碍的发展中可能是关键的。研究结果将显著提高我们对基因如何以增加精神和神经发育障碍风险的方式塑造神经发育轨迹的理解。最终，确定参与大脑发育的基因有可能显着改善诊断，指导环境风险因素的研究工作，并为患有精神和神经发育疾病的个体产生全新的治疗可能性。

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. PUBLIC HEALTH RELEVANCE: The primary goal of the current application is to identify common and rare genetic variants which predict early brain development in humans; a period which may be critical in the development of psychiatric and neurodevelopmental disorders such as autism, schizophrenia, intellectual disability and attention-deficit disorder. Results will significantly improve our understanding of how genes shape neurodevelopmental trajectories in a way which increases the risk for psychiatric and neurodevelopmental disorders. Ultimately, identifying the genes involved in brain development has the potential to significantly improve diagnosis, guide research efforts into environmental risk factors, and generate completely new treatment possibilities for individuals with psychiatric and neurodevelopmental conditions.