The genomic bridge project (GBP)

描述（由申请人提供）：该职业发展奖（K01）将为候选人提供必要的技能，以开发一个独立的研究项目，使用流行病学方法来识别神经精神疾病的生物学信息决定因素。虽然目前的证据表明，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遗传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验证以下假设：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影响行为和认知多个领域的人群变异。除此之外，该提案还研究了不同类型和严重程度的紊乱行为共享遗传影响的程度，或者是基因组桥接的程度。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对未来研究的个体进行分类，并加快特异性靶向治疗开发的步伐。该奖项的培训部分以麻省总医院的分析和转化遗传学部门为中心，旨在为候选人提供实现其独立研究和职业目标以及完成K01研究目标所需的技能。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的背景，但在使用可测量的遗传变量或发育方法研究精神表型方面没有受过训练。因此，她将在两个领域接受国际公认的专家的培训：1)统计遗传学，由马克·戴利博士指导；2)精神神经发育障碍的轨迹，由埃兹拉·苏瑟博士指导。在这些培训领域，罗宾逊博士将培养分析常见和罕见遗传变异的技能，并将这些技术与用于检查整个生命过程中的神经精神表型的策略相结合。她将通过课程作业在各个领域接受培训；与博士进行个人训练。Daly、Susser和7位专家顾问；参加会议;并监督研究项目。培训目标将应用于该奖项的研究部分，名为“基因组桥项目”（Genomic Bridge Project）。Robinson， Daly和Susser来验证上述假设。这些研究使用的数据来自世界上两个最大的、个体基因分型的一般人群数据集，双胞胎早期发展研究（TEDS）和雅芳父母和儿童纵向研究（ALSPAC），这些数据集从童年到青春期的行为已经被深深地表型化了。这些培训和研究项目将共同构成罗宾逊博士将提交的R01提案的基础

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.