The genomic bridge project (GBP)

描述(由申请人提供)：这一职业发展奖(K01)将为候选人提供必要的技能，以开发一个独立的研究计划，使用流行病学方法来确定神经精神疾病的生物信息决定因素。尽管目前的证据表明，遗传对神经精神表型的影响跨越了DSM-IV的界限，但与自闭症、精神分裂症和双相情感障碍相关的常见或罕见的基因变异对普通人群行为和认知的影响程度尚不清楚。当前提案的总体目标是检验以下假设：1)严重紊乱和亚临床行为障碍之间存在遗传联系；2)增加DSM-IV障碍风险的遗传变异在行为和认知的多个领域影响群体差异。换句话说，这项建议检查了不同类型和严重程度的障碍行为分享遗传影响的程度，或者是基因桥接的程度。这些研究的发现将有助于建立一系列可能共享潜在病理生理学的行为。这种与病因相关的行为系统的识别将有助于为未来的研究研究对个体进行分类，并加快特定靶向治疗开发的步伐。拟议奖项的培训部分以马萨诸塞州综合医院的分析和翻译遗传学部门为中心，旨在为应聘者提供必要的技能，以实现她的独立研究和职业目标，以及完成K01研究目标。罗宾逊博士有行为遗传学(双胞胎研究)和儿童行为障碍流行病学方面的背景，但没有接受过使用测量的遗传变量或精神病学表型的发育方法方面的培训。因此，她将在两个新领域接受国际公认的专家的培训：1)由Mark Daly博士指导的统计遗传学，以及2)由Ezra Susser博士指导的精神神经发育障碍的轨迹。在这些培训领域内，罗宾逊博士将发展分析常见和罕见基因变异的技能，并将这些技术与在整个生命过程中检查神经精神表型的策略相结合。她将通过课程作业、与Daly博士、Susser博士和七名专家顾问一起进行个人培训、出席会议和监督研究项目来接受每个领域的培训。培训目标将应用于该奖项的研究部分，名为基因组桥项目：由Robinson、Daly和Susser博士设计的三项研究，以检验上述假设。这些研究使用了世界上两个最大的、个别基因分型的一般人口数据集的数据，在这些数据集中，行为从童年到青春期都有很深的表型，这两个数据集是双胞胎早期发展研究(TEDS)和雅芳亲子纵向研究(ALSPAC)。这些培训和研究项目将共同构成R01提案的基础，罗宾逊博士将 在戴利博士和苏瑟博士的持续指导下，在获奖期的第四年和第五年进行准备。R01将利用职业发展奖期间完成的培训和研究，调查普通人群中遗传对行为和认知障碍系统的影响。

DESCRIPTION (provided by applicant): This Career Development Award (K01) will provide the candidate with the necessary skills to develop an independent research program that uses epidemiologic methods to identify biologically-informative determinants of neuropsychiatric disease. Although current evidence suggests that genetic influences on neuropsychiatric phenotypes cross DSM-IV boundaries, the extent to which either common or rare genetic variants associated with autism, schizophrenia, and bipolar disorder affect behavior and cognition in the general population is not well understood. The overall aim of the current proposal is to test the hypotheses that: 1) there is a genetic link between severely disordered and subclinical behavioral impairments and 2) the genetic variants that increase risk for DSM-IV disorders influence population variation in multiple domains of behavior and cognition. Stated otherwise, this proposal examines the extent to which different types and severities of disordered behavior share genetic influences, or are genomically-bridged. The findings from these studies will help establish sets of behavior that are likely to share underlying pathophysiology. The identification of such etiologically-linked systems of behavior will aid in th classification of individuals for future research studies and accelerate the pace of specifically-targeted treatment development. The training component of the proposed award, centered in the Analytic and Translational Genetics Unit at Massachusetts General Hospital, is designed to provide the candidate with the skills necessary to reach her independent research and career goals, as well as to complete the K01 research aims. Dr. Robinson has a background in behavior genetics (twin studies) and the epidemiology of childhood behavioral disorders, but no training in the use of measured genetic variables or developmental approaches to psychiatric phenotypes. She will accordingly be trained in two novel areas by internationally-recognized experts in each field: 1) statistical genetics, mentored by Dr. Mark Daly, and 2) trajectories of psychiatric neurodevelopmental disorders, mentored by Dr. Ezra Susser. Within these training areas, Dr. Robinson will develop skills in the analysis of both common and rare genetic variation, and integrate those techniques with strategies employed to examine neuropsychiatric phenotypes across the lifecourse. She will be trained in each area through course work; individual training with Drs. Daly, Susser, and seven expert consultants; conference attendance; and supervised research projects. The training aims will be applied in the research component of the award, titled the Genomic Bridge Project: three studies designed by Drs. Robinson, Daly, and Susser to test the hypotheses above. The studies use data from the two largest, individually-genotyped general population datasets in the world in which behavior has been deeply phenotyped from childhood through adolescence, the Twins Early Development Study (TEDS) and the Avon Longitudinal Study of Parents and Children (ALSPAC). Together, these training and research projects will constitute the basis for an R01 proposal that Dr. Robinson will prepare in the fourth and fifth years of the award period, under continued guidance from Drs. Daly and Susser. This R01 will employ the training and research completed during the Career Development Award period to investigate the genetic influences on systems of behavioral and cognitive impairment in the general population.