Amish Connectome Project on Mental Illness

 描述(由申请人提供)：Amish Connectome Project(ACP)将通过表征大脑回路及其与精神行为和症状维度的关系，将人类Connectome Project(HCP)扩展到精神疾病。我们建议收集旧秩序阿米什(OOA)成年人的HCP连接组学和全基因组测序数据，这些成人来自跨越诊断界限的多代多重精神障碍家庭。有两个或更多成员患有严重DSM-5疾病的大型核心家庭将被招募，使用扩展到研究领域标准(RDoC)的完整HCP寿命成像和行为方案进行表型鉴定。面向连接的非侵入性神经成像方法的出现，为了解大脑的内部工作机制提供了新的线索。大脑的功能和结构连接体在调节从基因到神经系统再到精神疾病的途径中发挥着关键作用。将基因--&gt；Connectome HCP方法扩展到基因--&gt；Connectome--&gt；人类疾病中的精神障碍为确定遗传性精神障碍的遗传基础增加了巨大的机会。ACP提供了一种独特的高效和强大的研究设计，这是成功突破的关键。ACP将从群体隔离中研究多代大家庭，这是一个强大的统计设计，用于发现连接特征和精神障碍之间的遗传联系。OOA样本在相对遗传一致性方面是独一无二的，其祖先记录在NIH数据库中，可追溯到有限的创始人的14代。这一样本也是独一无二的，因为它在教育背景、生活和工作条件、社会经济地位以及受非法药物的影响大大减少方面相对一致。OOA社区成员的这些独特特征，加上他们的大家庭规模，使OOA成为研究具有家族遗传模式的精神障碍中改变大脑连通性的遗传因素的强大人群样本。我们将通过精神病学诊断、广泛的症状以及行为和认知的RDoC维度评估来扩展HCP协议。所有参与者的全基因组数据将通过下一代测序和以家族为基础的Gwas数据来获得。这些数据将与大型研究界共享，同时保护参与者的隐私、机密性和福利，并特别注意保护OOA社区的福利。OOA中的医学遗传学发现通常会在普通人群样本中复制，并转化为临床实践。我们受到启发，通过共享数据努力创造机会，允许在大脑连接组和精神疾病方面复制SuH的成功，并组建了一个高效的团队来领导这一努力。

 DESCRIPTION (provided by applicant): The Amish Connectome Project (ACP) will extend the Human Connectome Project (HCP) to mental illnesses by characterizing brain circuitry and its relation to psychiatric behavior and symptom dimensions. We propose to collect HCP connectomics and whole genome sequencing data in Old Order Amish (OOA) adults recruited from multigenerational families with multiplex mental disorders spanning diagnostic boundaries. Large nuclear families with two or more members with major DSM-5 disorder will be recruited for phenotyping using the full HCP lifespan imaging and behavioral protocol expanded to Research Domain Criteria (RDoC) standard. The advent of non-invasive connectivity-oriented neuroimaging methods has shed new light onto the inner workings of the brain. The brain's functional and structural connectome plays key roles in regulating the pathway from genes to neural systems to mental illnesses. Extending the gene -->connectome HCP approach to gene -->connectome -->mental disorder in HCP-Human Disease adds tremendous opportunity to identify genetic underpinning of heritable mental disorders. ACP offers a uniquely efficient and powerful study design that is critical for a successful breakthrough. The ACP will study large, multigenerational families from a population isolate, which is a powerful statistical design for discovery of genetic linkage between connectomic traits and mental disorders. The OOA sample is unique in its relative genetic uniformity, with ancestry recorded in the NIH database and traceable back fourteen generations to limited founders. This sample is also unique because of its relative uniformity in educational background, life and work conditions, socioeconomic status and much reduced influence by illicit drugs. These unique characteristics of OOA community members, combined with their large family size, makes the OOA a powerful population sample to study the genetic factors that alter cerebral connectivity in mental disorders with familial pattern of inheritance. We will expand upon HCP protocol with the psychiatric diagnosis, broad symptom and RDoC dimensional assessments of behavior and cognition. Whole genome data will be obtained for all participants through next generation sequencing and family-based imputation of GWAS data. These data will be shared with the large research community while protecting the privacy, confidentiality and welfare of participants, with special attention given to protect the welfare of the OOA community. Medical genetic discoveries in OOA have routinely been replicated in general population samples and translated to clinical practice. We are inspired to create opportunities to allow repetitions of suh success in brain connectome and in mental illness through shared data effort, and have assembled an efficient team to lead this endeavor.