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

项目总结 国际大脑和行为拷贝数变异联盟(IBBC-CNVS)是一项合作 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的努力。22q11.2 和16p11.2基因座与终生神经精神疾病的显著风险相关。这个 临床表现是不同的，表现为一系列发育性神经精神障碍， 包括注意力缺陷多动、焦虑、自闭症谱系和精神病谱系障碍。拿走 根据已知的、同质性的遗传病因确定患者的“遗传学优先”方法将允许 美国将克服特发性发育中遗传和表型复杂性带来的障碍 神经精神障碍。我们假设CNV在精神病理学上发挥着很大的主要作用，但 在CNV携带者中观察到的精神病理的性质和程度是多因素的，贡献来自 其他稀有和常见的遗传变异，以及环境因素。因此，剖析 主要CNV击打以及其他稀有和常见变异体对心电容量测量的影响 精神病理学可以阐明遗传机制对精神疾病和 建立风险预测模型。值得注意的是，CNV的精神病理学的表现和过程类似于 特发性精神障碍的这些特征。因此，除了被调查的特定遗传综合征外，这样的 跨CNV努力将确定发育性神经精神障碍的趋同风险机制 与更广泛的人群相关。 我们建议剖析精神病、社会情绪处理和神经认知的维度测量， 以及他们的遗传和环境修饰物，以阐明神经精神疾病的风险架构 CNV携带者的疾病。与神经精神病学相关的维度测量的前瞻性评估 疾病将应用于具有22q11.2和16p11.2缺失和重复的2000人队列 (每组500人)及其亲属。此外，还将评估明确的精神病学诊断 在CNV携带者中。未来表型鉴定的招募将利用现有的携带这些基因的大型队列 相互的CNV，其中许多已经被确定并具有一系列的表型特征 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 已排序。我们还将利用现有的最大病例对照样本中的基因数据。 在PGC中被诊断为SZ、ASD和ADHD。最后，对家族子集的常见变体进行了分析 成员们将允许我们通过探索复杂遗传遗传的模型来补充我们的初步分析 在携带CNV的扩展家系中。我们构思如此大规模研究的能力利用了我们的 现有的成功协作、互补的专业知识和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.