Neuroimaging genetics to study social cognitive deficits in ASD and schizophrenia

描述(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，可能有一些共同的病因机制。虽然这两种疾病在发育轨迹和临床表现方面明显不同，但人们很早就认识到，社会认知缺陷存在相当大的重叠。因此，社会认知缺陷的这种重叠是反映了共同的病因机制，还是由于这两种疾病之间的共病或误诊而表现出表面上的相似之处，这是一个非常合理但仍未得到解答的问题。申请者Phil H.Lee博士建议通过对ASD和SCZ的综合神经成像遗传学研究来解决这一研究问题，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来的努力，Lee博士现在已经获得了大规模的基因数据(全基因组SNPs，N=32,921；全外显子组测序数据，N=7,000)和一个独立的神经成像队列，包括ASD、SCZ病例和健康对照组，他们拥有一套丰富的脑成像和行为测量(N=3,752)。利用这些异常强大的资源，她将调查常见的ASD和SCZ遗传风险负担与社会认知(ASD)和精神分裂症(SCZ)功能的脑成像/行为指标之间的预测关系。因此，这项研究的成功完成将：(1)阐明多个水平上的遗传变异(即常见和罕见的变异)如何影响大脑结构/功能和超越传统病因学界限的核心社会缺陷的发展；(2)开发具有高度创新性和普遍适用于复杂特征研究的新的分析策略；以及(3)为开发基于生物学的预防和补救这种核心脑缺陷的策略奠定基础。李博士的职业目标是通过对遗传和神经影像数据的综合分析，研究自闭症和精神分裂症等严重神经发育障碍的病因。这项申请建立在她在精神病学统计遗传学方面的博士后培训基础上，以各种神经精神障碍的全基因组关联研究为中心。在努力完成拟议研究的同时，李博士将接受世界领先的计算遗传学、临床精神病学和认知神经科学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成像基因研究，确保研究工作的有效性、可靠性和临床适用性，最重要的是，能够通过制定循证预防、诊断和治疗策略，将研究结果转化为巨大的公共健康利益。

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.