Genomics of Developmental Trajectories in Twins

描述(由申请人提供)：大量的研究精力一直致力于证明遗传对儿童发育精神病理学的影响的重要性。到目前为止，可以提出一个令人信服的论点，即所有的发育性精神病都至少部分地受到遗传因素的影响。行为遗传学方法对某些表型(注意缺陷多动障碍)的遗传率估计高达80%，大多数疾病受到遗传和环境影响(如焦虑/抑郁)的影响程度大致相等。对特定基因组影响的研究包括了各种各样的分子方法。在这些研究中，最常见的方法是研究可能的候选基因与“关联研究”中的兴趣障碍之间的关系。到目前为止，这些研究已经产生了适度的可复制的结果，导致了一种看法，即需要使用大样本的多种方法来更好地理解遗传因素如何导致复杂的疾病，如儿童发育过程中的精神病理。为了寻找线索，研究人员使用了连锁研究和最近的基因组广域关联(GWAS)研究。最近的研究证明，CNV区域的基因比非CNV区域的基因表达更具变异性，而且CNV对整个转录组具有“全球影响”(3)。在单纯性孤独症的研究中，5项研究报告了在单纯性孤独症的研究中，新生CNV的数量增加，这导致了在发展精神病理学方面的重大发现。CNV效应，无论是从头开始的还是基于家系的，都会导致复杂的特征，如儿童ADHD、强迫症(OCD)、对立违抗性障碍(ODD)等常见的发展性精神病，目前尚未有文献报道。这项申请提出了第一个单核苷酸多态(SNP)/拷贝数变异和(CNV)基因组范围的常见儿童精神病理学研究，使用扩展的双胞胎兄弟姐妹家庭研究设计。已经从从出生到22岁的儿童和兄弟姐妹及其父母的大样本(N=4414)中收集了DNA。这项研究将使我们能够确定新的基因对儿童精神疾病的影响，这反过来将导致改进诊断和治疗方法。 公共卫生相关性：这项申请提出了第一个单核苷酸多态(SNP)/拷贝数变异和(CNV)全基因组关联研究，使用扩展的双胞胎兄弟姐妹家庭研究设计对常见的儿童精神病理学进行研究。已经从从出生到22岁的儿童和兄弟姐妹及其父母的大量样本中收集了DNA。这项研究将使我们能够确定新的基因对儿童精神疾病的影响，这反过来将导致改进诊断和治疗方法。

DESCRIPTION (provided by applicant): A tremendous amount of research energy has been dedicated to demonstrating the importance of genetic influences on developmental psychopathologies in children. To date a convincing argument can be made that all of the developmental psychopathologies are influenced, at least in part, by genetic factors. Behavioral genetic approaches have yielded heritability estimates as high as 80% for some phenotypes (Attention Deficit Hyperactivity Disorder), with the majority of disorders influenced in roughly equal parts by genetic and environmental influences (e.g. Anxious/ Depression). The search for the specific genomic influences has included a wide variety of molecular approaches. Among these the most common approach has been to study the relations between putative candidate genes and the disorder of interest in 'association studies'. To date these studies have yielded modest replicable results leading to the perception that multiple approaches using large samples will be needed to better understand how genetic factors contribute to complex disorders like the child psychopathologies across development. Investigators have used linkage and more recently Genome Wide Association (GWAS) studies in order to search the entire genome for clues. Recent studies provide evidence that genes in CNV regions are more variably expressed than genes in non- CNV regions and further that CNVs have 'global influence' on the entire transcriptome (3). CNV studies in singletons have led to significant discoveries in developmental psychopathology with 5 studies reporting an increased number of de novo CNV's in the study of Autism simplex cases (4). CNV effects, whether de novo or pedigree based, contributing to risk for complex traits such as common developmental psychopathology like childhood ADHD, Obsessive Compulsive Disorder (OCD), Oppositional Defiant Disorder (ODD) have not yet been reported in the literature. This application proposes the first single nucleotide polymorphism (SNP)/copy number variation and (CNV) genome-wide association study of common childhood psychopathologies using an extended twin-sibling family study design. DNA has already been collected from a large sample (N=4,414) of children and siblings who have been followed from birth until age 22 and their parents. This study will allow us to identify new genetic influences on child psychiatric illness which in turn will lead to improved diagnostic and treatment approaches. PUBLIC HEALTH RELEVANCE: This application proposes the first single nucleotide polymorphism (SNP)/copy number variation and (CNV) genome-wide association study of common childhood psychopathologies using an extended twin-sibling family study design. DNA has already been collected from a large sample of children and siblings who have been followed from birth until age 22 and their parents. This study will allow us to identify new genetic influences on child psychiatric illness which in turn will lead to improved diagnostic and treatment approaches.