Neuroimaging genetics to study social cognitive deficits in ASD and schizophrenia

神经影像遗传学研究自闭症谱系障碍和精神分裂症的社会认知缺陷

• 批准号: 8846139
• 负责人: Phil H. Lee
• 金额: $ 11.85万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-06 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8846139
• 关键词: Address; Autistic Disorder; Award; Behavior; Behavioral; Biological; Biology; Brain; Brain imaging; Clinical; Cognition; Cognitive; Cognitive deficits; Collection; Comorbidity; Complex; DNA; Data; Data Set; Development; Diagnosis; Disease; Empathy; Ensure; Epidemiologic Studies; Epidemiology; Etiology; Eye; Foundations; Functional Magnetic Resonance Imaging; Genes; Genetic; Genetic Markers; Genetic Predisposition to Disease; Genetic Risk; Genetic Variation; Genetic study; Genomics; Genotype; Goals; Health; Health Benefit; Image; Individual; Knowledge; Light; Measures; Medial; Medical Genetics; Meta-Analysis; Methods; Mind; Neurobiology; Neurodevelopmental Disorder; Neurosciences; Pathway interactions; Personality; Prevention; Psychiatry; Public Health; Reading; Research; Research Domain Criteria; Research Priority; Research Project Grants; Research Training; Resources; Rest; Risk; Schizophrenia; Staging; Structure; Suggestion; Susceptibility Gene; Temperament; Thick; Transcend; Translating; Validity and Reliability; Variant; Work; autism spectrum disorder; base; behavior measurement; burden of illness; career; clinical application; cognitive function; cognitive neuroscience; cohort; design; disorder risk; effective therapy; endophenotype; evidence base; exome sequencing; functional disability; genetic analysis; genetic variant; genome wide association study; genome-wide; indexing; innovation; insight; neural circuit; neural correlate; neuroimaging; neuropsychiatry; next generation sequencing; novel; post-doctoral training; rare variant; relating to nervous system; remediation; risk variant; skills; social; social cognition; targeted treatment; theories; trait; treatment strategy

DESCRIPTION (provided by applicant): Recent advances in epidemiologic, brain-imaging, and genomic studies suggest that autism spectrum disorder wo of the most heritable and pervasive neurodevelopmental disorders, may share some common etiologic mechanisms. While the two disorders are markedly distinct in terms of developmental trajectories and clinical presentations, it has long been recognized that there is considerable overlap of social cognitive deficits. It is thus a highly plausible yet unanswered question whether this overlap in social cognitive deficits reflects common etiological mechanisms, or represents superficial similarities due to comorbidity or misdiagnosis between these two illnesses. The applicant, Dr. Phil H. Lee proposes to address this research question through integrative neuroimaging genetic studies of ASD and SCZ, starting from genes to neural circuits, and ultimately to behavioral measures of social cognition. Owing to years' of efforts from worldwide collaborators, Dr. Lee now has access to large-scale genotype data (for genome-wide SNPs, N=32,921; for whole-exome-sequencing data, N=7,000) and an independent neuroimaging cohort of ASD, SCZ cases and healthy controls for whom a rich set of brain imaging and behavioral measures are available (N=3,752). Using these exceptionally powerful resources, she will investigate predictive relationships between common ASD and SCZ genetic risk burden and brain imaging/behavioral indexes of social cognitive (ASD) and schizophrenia (SCZ), t functioning. The successful completion of this study will thus: (1) clarify how genetic variations at multiple levels (i.e., common and rare variants) influence brain structure/function and the development of core social deficits transcending traditional nosologic boundaries; (2) develop novel analytic strategies that are highly innovative and of general applicability to the studies of complex traits; and (3) lay th foundation for the development of biology-based prevention and remediation strategies for this core brain deficit. Dr. Lee's career goal is to study the etiologic pathways of severe neurodevelopmental disorders, such as autism and schizophrenia, using an integrative analysis of genetic and neuroimaging data. This application builds on her postdoctoral training in psychiatric statistical genetics, centered on genome-wide association studies of a variety of neuropsychiatric disorders. While working towards accomplishing the proposed study, Dr. Lee will receive in-depth research training from world's leading experts in computational genetics, clinical psychiatry, and cognitive neuroscience. This K99 Award will thus provide her with crucial and timely support to develop into an independent translational geneticist, who can effectively design and conduct neuroimaging genetic studies, ensure the validity, reliability and clinical applicability of the research work, and most importantly, is capable of translating the research findings into great public health benefits through the development of evidence-based prevention, diagnosis, and treatment strategies.

描述（由申请人提供）：流行病学、脑成像和基因组研究的最新进展表明，自闭症谱系障碍是最易遗传和最普遍的神经发育障碍之一，可能具有一些共同的病因机制。虽然这两种疾病在发展轨迹和临床表现方面明显不同，但长期以来人们一直认为社会认知缺陷有相当大的重叠。因此，这是一个非常合理但尚未回答的问题，这种重叠的社会认知缺陷是否反映了共同的病因机制，或代表表面的相似性，由于合并症或误诊之间的这两种疾病。申请人Phil H. Lee建议通过ASD和SCZ的综合神经影像遗传学研究来解决这个研究问题，从基因到神经回路，最终到社会认知的行为测量。由于全球合作者多年的努力，Lee博士现在可以获得大规模的基因型数据（全基因组SNP，N= 32，921;全外显子组测序数据，N= 7，000）和一个独立的ASD，SCZ病例和健康对照的神经影像学队列（N= 3，752）。利用这些异常强大的资源，她将研究常见ASD和SCZ遗传风险负担与社会认知（ASD）和精神分裂症（SCZ）的脑成像/行为指数之间的预测关系。因此，这项研究的成功完成将：（1）阐明多个水平的遗传变异（即，常见和罕见的变异）影响大脑结构/功能和超越传统疾病分类学界限的核心社会缺陷的发展;（2）开发高度创新和普遍适用于复杂特征研究的新分析策略;（3）为开发基于生物学的预防和补救策略奠定基础。李博士的职业目标是研究严重神经发育障碍的病因学途径，如自闭症和精神分裂症，使用遗传和神经影像学数据的综合分析。这个应用程序建立在她的精神统计遗传学博士后培训，集中在各种神经精神疾病的全基因组关联研究。在努力完成这项研究的同时，李博士将接受来自计算遗传学、临床精神病学和认知神经科学领域世界领先专家的深入研究培训。因此，K99奖将为她提供关键和及时的支持，使她能够发展成为一名独立的翻译遗传学家，能够有效地设计和进行神经影像遗传学研究，确保研究工作的有效性，可靠性和临床适用性，最重要的是，能够通过发展循证预防，诊断，和治疗策略。