7/9 Rare Genetic Disorders as a Window into the Genetic Architecture of Mental Disorders

项目概要 国际脑与行为拷贝数变异联盟 (IBBC-CNVs) 是一个协作组织 由 9 个在表型组学和基因组学方面具有互补经验和专业知识的机构共同努力。 22q11.2 和 16p11.2 位点与整个生命周期中神经精神疾病的显着风险相关。的 临床表现多种多样，表现为一系列发育性神经精神疾病， 包括注意力缺陷多动症、焦虑症、自闭症谱系障碍和精神病谱系障碍。服用 基于已知的同质遗传病因来确定患者的“遗传学优先”方法将允许 我们克服特发性发育的遗传和表型复杂性所造成的障碍 神经精神疾病。我们假设 CNV 对精神病理学发挥着巨大的主效应，但 在 CNV 携带者中观察到的精神病理学的性质和程度是多因素的，其中包括 其他罕见和常见的遗传变异以及环境因素。因此，剖析 主要 CNV 命中以及其他罕见和常见变异对维度测量的影响 精神病理学可以阐明遗传机制对精神疾病的综合作用， 建立风险预测模型。值得注意的是，CNV 中精神病理学的表现和过程类似于 特发性疾病的这些特征。因此，除了所研究的特定遗传综合征之外，这样的 跨 CNV 的努力将确定发育性神经精神疾病的趋同风险机制，这些疾病 与更广泛的人群相关。 我们建议剖析精神病、社会情感处理和神经认知的维度测量， 及其遗传和环境调节剂，以阐明神经精神疾病的风险结构 CNV 携带者的疾病。使用与神经精神病学相关的维度测量进行前瞻性评估 该疾病将应用于 2000 名 22q11.2 和 16p11.2 缺失和重复个体的队列 （每组 500 人）及其亲属（尽可能）。此外，还将评估分类精神病学诊断 在 CNV 载体中。前瞻性表型的招募将利用现有的携带这些的大型队列 相互的 CNV，其中许多已被确定并具有一系列表型特征 措施。新的全基因组测序（WGS）将在尚未进行的 CNV 携带者中进行 已测序。我们还将利用来自最大可用病例对照样本的现有遗传数据 在 PGC 中被诊断患有 SZ、ASD 和 ADHD。最后，对家庭子集的常见变异进行分析 成员将使我们能够通过探索复杂的遗传模型来补充我们的初步分析 在携带 CNV 的扩展谱系中。我们有能力构思如此大规模的研究，充分利用了我们的能力 现有的成功合作、互补的专业知识以及实现这些目标的机构承诺 目标。

PROJECT SUMMARY The International Consortium on Brain and Behavior Copy Number Variants (IBBC-CNVs) is a collaborative effort of 9 institutions with complementary experience and expertise in phenomics and genomics. The 22q11.2 and 16p11.2 loci are associated with significant risk for neuropsychiatric disorders across the lifespan. The clinical presentations are heterogeneous, manifesting in a range of developmental neuropsychiatric disorders, including Attention Deficit Hyperactivity, Anxiety, Autism Spectrum, and Psychosis Spectrum Disorders. Taking a `genetics first' approach of ascertaining patients based on known, homogeneous genetic etiologies will allow us to overcome barriers posed by the genetic and phenotypic complexity of idiopathic developmental neuropsychiatric disorders. We postulate that CNVs exert a large main effect on psychopathology, but the nature and degree of psychopathology observed in CNV carriers is multifactorial, with contributions from additional rare and common genetic variants, as well as environmental factors. Therefore, dissecting the effects of major CNV hits as well as additional rare and common variants on dimensional measures of psychopathology can elucidate the combined contribution of genetic mechanisms to psychiatric conditions and build models of risk prediction. Notably, the presentation and course of psychopathology in the CNVs resemble these features in idiopathic disorders. Therefore, beyond the specific genetic syndromes investigated, such a cross-CNV effort will identify convergent risk mechanisms for developmental neuropsychiatric disorders that are of relevance to the broader population. We propose to dissect dimensional measures of psychosis, social-emotional processing and neurocognition, and their genetic and environmental modifiers, to elucidate the architecture of risk for neuropsychiatric disorders in CNV carriers. Prospective evaluation with dimensional measures relevant to neuropsychiatric disorders will be applied to a cohort of 2000 individuals with 22q11.2 and 16p11.2 deletions and duplications (500 per group) and their relatives as feasible. In addition, categorical psychiatric diagnoses will be assessed in CNV carriers. Recruitment for prospective phenotyping will leverage existing large cohorts that carry these reciprocal CNVs, many of whom have already been ascertained and characterized with a range of phenotypic measures. New whole genome sequencing (WGS) will be performed in CNV carriers that have not yet been sequenced. We will also utilize existing genetic data from the largest available case-control samples diagnosed with SZ, ASD, and ADHD in the PGC. Finally, analysis of common variants for a subset of family members will allow us to complement our primary analysis by exploring models of complex genetic inheritance in extended pedigrees that carry CNVs. Our ability to conceive such a large scale study capitalizes on our existing successful collaborations, complementary expertise, and institutional commitments to achieve these goals.