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。迄今为止，一个令人信服的论点是，所有的发展性精神病理学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%，大多数疾病受遗传和环境影响的程度大致相等（例如焦虑/抑郁）。对特定基因组影响的研究包括各种各样的分子方法。其中最常见的方法是在“关联研究”中研究假定的候选基因与感兴趣的疾病之间的关系。到目前为止，这些研究已经产生了适度的可复制结果，导致人们认为，需要使用大样本的多种方法来更好地了解遗传因素如何导致复杂的疾病，如儿童精神病理学。研究人员使用连锁和最近的全基因组协会（GWAS）研究来搜索整个基因组的线索。最近的研究提供证据表明，CNV区域的基因比非CNV区域的基因表达更可变，并且CNV对整个转录组具有“全局影响”(3)。对单胎婴儿的CNV研究在发育精神病理学方面有重大发现，有5项研究报告在单纯性自闭症病例的研究中，新生CNV的数量有所增加(4)。CNV效应，无论是从头开始的还是基于谱系的，对复杂特征的风险有贡献，如儿童多动症、强迫症（OCD）、对立违抗性障碍（ODD）等常见的发展性精神病理学，文献中尚未报道。本申请提出了第一个单核苷酸多态性(SNP)/拷贝数变异和（CNV）全基因组关联研究常见的儿童精神病理使用扩展双胞胎兄弟姐妹家庭研究设计。已经从一个大样本（N=4,414）的儿童和兄弟姐妹中收集了DNA，这些儿童和兄弟姐妹从出生到22岁以及他们的父母。这项研究将使我们能够确定对儿童精神疾病的新的遗传影响，从而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.