Neurocognition as an endophenotype in bipolar disorder

描述（由申请人提供）：本申请是指导患者导向职业发展奖（K23）的第三次提交，旨在支持候选人发展成为一名独立的研究者，能够将神经认知方面的坚实背景和训练与分子遗传学工具相结合，用于基于家庭的双相情感障碍（BPD）研究。在心境不佳期间，BPD患者持续的神经认知缺陷引起了人们对神经认知功能障碍作为一种中间表型或内表型的兴趣，以研究其疾病易感位点；然而，我们对其熟悉性或遗传性的认识存在一个关键的空白。家族内聚集的内表型标准尚未在未受影响的BPD患者一级亲属中得到令人信服的证明。候选人建议首先获得收集和分析数据所需的知识和培训，以提供作为BPD内表型的神经认知的关键验证和改进，并随后对此目标进行初步研究。发展规划有三个主要目标：1)拓展和完善BPD神经认知在分子遗传学研究中的应用；2)获得家庭研究方法的经验，包括对分子遗传学模型的理解和统计方法的理解，以整合定量临床数据和分子遗传学数据；3)获得BPD神经认知功能障碍遗传基础的直接研究经验和初步数据。为了实现这些目标，已经准备了一个全面的教学计划。此外，候选人将在BPD患者及其未受影响的兄弟姐妹中进行基于家庭的神经认知研究。该研究计划收集100名未受影响的BPD患者的兄弟姐妹、100名稳定的BPD患者和100名人口统计学匹配的健康志愿者的全面神经认知数据。大规模实施这种可行的检测方法的可行性将是阐明BPD遗传基础的重要一步。本申请中描述的职业发展活动和研究的完成预计将为候选人提供知识和经验，以发展成为一名具有专业知识的独立研究者，进行高质量的基于家庭的研究，将神经认知纳入双相情感障碍的分子遗传研究。

DESCRIPTION (provided by applicant): This application is a third submission for a Mentored Patient-oriented Career Development Award (K23) is to support the candidate's development into an independent investigator capable of integrating a solid background and training in neurocognition with the tools of molecular genetics for use in family-based studies of bipolar disorder (BPD). Persistent neurocognitive deficits in BPD during periods of euthymia have aroused interest in neurocognitive dysfunction as an intermediate phenotype, or endophenotype, for studies of its disease susceptibility loci; however, a critical gap in our knowledge exists regarding its familiality or heritability. The endophenotypic criterion of aggregation within families has not yet been convincingly demonstrated among unaffected first-degree relatives of BPD patients. The candidate proposes to first gain the knowledge and training required to collect and analyze data to provide critical validation and refinement of neurocognition as an endophenotype for BPD and to subsequently conduct preliminary research toward this goal. The development plan has three major goals: 1) To expand and refine the candidate's knowledge of the neurocognition of BPD with regard to its use in molecular genetic studies 2) To gain experience in family study methodology including a significant emphasis on understanding molecular genetic models and statistical approaches to integrate quantitative clinical data and molecular genetic data, and 3) To acquire direct research experience and preliminary data on the genetic underpinnings of neurocognitive dysfunction in BPD. To accomplish these aims, a comprehensive didactic program has been prepared. In addition, the candidate will conduct a family-based study of neurocognition in patients with BPD and their unaffected siblings. The research plan proposes to collect comprehensive neurocognitive data in 100 unaffected siblings of BPD patients, 100 stable BPD patients, and 100 demographically-matched healthy volunteers. The feasibility of large-scale implementation of such a viable assay would represent a vital step toward elucidating the genetic underpinnings of BPD. The career development activities and completion of the research study described in this application are expected to provide the candidate with the knowledge and experience to develop into an independent investigator with the expertise to conduct high quality family- based studies that incorporate neurocognition into molecular genetic studies of bipolar disorder.