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性精神病理学的重要性。到目前为止，一个令人信服的论点是，所有的发展性精神病理学都受到遗传因素的影响，至少部分是这样。行为遗传学的方法已经产生了遗传性估计高达80%的一些表型（注意缺陷多动障碍），与大多数疾病的影响，在大致相等的部分遗传和环境的影响（例如焦虑/抑郁症）。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研究假定的候选基因和“关联研究”中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的结果，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。研究人员已经使用了连锁和最近的全基因组协会（GWAS）研究，以搜索整个基因组的线索。最近的研究提供证据表明，CNV区域中的基因比非CNV区域中的基因更易表达，并且进一步证明CNV对整个转录组具有“全局影响”（3）。在单例患者中进行的CNV研究已经在发育精神病理学方面取得了重大发现，5项研究报告了在单纯自闭症病例研究中新发CNV数量的增加（4）。CNV效应，无论是从头还是基于谱系，都有助于复杂特征的风险，如常见的发育性精神病理学，如儿童ADHD，强迫症（OCD），对立违抗性障碍（ODD）尚未在文献中报道。 本申请提出了第一个单核苷酸多态性（SNP）/拷贝数变异和（CNV）基因组范围内的关联研究常见的儿童精神病理学使用扩展的孪生兄弟姐妹家庭研究设计。DNA已经从一个大样本（N= 4，414）的儿童和兄弟姐妹中收集，这些儿童和兄弟姐妹从出生到22岁及其父母都被跟踪。这项研究将使我们能够确定新的遗传因素对儿童精神疾病的影响，这反过来将导致改善诊断和治疗方法。 公共卫生相关性：本申请提出了第一个单核苷酸多态性（SNP）/拷贝数变异和（CNV）基因组范围内的关联研究常见的儿童精神病理学使用扩展的孪生兄弟姐妹家庭研究设计。DNA已经从大量的儿童和兄弟姐妹样本中收集，这些儿童和兄弟姐妹从出生到22岁一直被跟踪，他们的父母也被跟踪。这项研究将使我们能够确定新的遗传因素对儿童精神疾病的影响，这反过来将导致改善诊断和治疗方法。

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.