Genetic & Environmental Risk Factors that Contribute to Childhood Psychopathology

描述（由申请人提供）：虽然人类行为表型总是异质的，但新出现的文献支持这样的假设，即遗传遗传性和环境影响都有助于儿童常见的行为状况和疾病。然而，遗传以及母亲压力、抑郁和焦虑影响儿童行为的途径仍然不清楚。利用一项公开的、无偏倚的全基因组关联研究（GWAS），我们确定了ADHD儿童中与儿童行为问题、注意力不集中、多动情绪症状、同伴问题和亲社会行为相关的基因多态性。我们假设，母亲在怀孕期间的精神疾病或其药物治疗可能会改变后代对后期精神病理的易感性，而遗传变异会增加后代患儿童精神病理的风险。这一假设将通过检测以下方面的关联来验证：1)基于证据的候选基因多态性与表型的前瞻性评估，怀孕期间患有精神疾病的妇女所生的高危儿童；2)这些候选基因在胎盘组织中的甲基化模式与这些儿童所测量的特征和行为；3)这些基因在胎盘组织中编码的mRNA的表达。本研究计划与教学课程以及与多学科指导团队的互动提供了一个旨在实现以下培训目标的培训平台：熟练掌握1)表型表征和儿童精神病理学的生物学基础2)生物信息学和生物统计学原理，因为它们适用于基于家庭的关联研究的设计，实施和分析3)与甲基化和基因表达分析相关的技术和方法问题，因为它们适用于精神遗传研究。在完成建议的项目和教育计划中描述的正式培训后，候选人将在开始独立的学术生涯方面取得重大进展。

DESCRIPTION (provided by applicant): While human behavioral phenotypes are invariably heterogeneous, an emerging literature supports the supposition that both genetic heritability and environmental influences contribute to behavioral conditions and disorders commonly diagnosed in children. Nevertheless, the pathways by which genetics, as well as maternal stress, depression and anxiety influence childhood behavior remain obscure. Utilizing a publically available, unbiased genome-wide association study (GWAS), we identified polymorphisms in genes associated with measures of childhood conduct problems, inattention, hyperactivity emotional symptoms, peer problems and prosocial behavior in children with ADHD. We hypothesize that maternal mental illness during pregnancy, or its pharmacological treatment, may alter the offspring's vulnerability to later psychopathology and that genetic variation will increase the offspring's risk developing childhood psychopathology. This hypothesis will be tested by examining associations of 1) polymorphisms in evidence-based candidate genes with phenotypes prospectively-evaluated, high-risk children born to women who were mentally ill during pregnancy 2) methylation patterns of those candidate genes in placental tissue with traits and behaviors measured in these children, and 3) the expression of mRNA encoded by those genes in placental tissue. This research proposal along with the didactic coursework and interaction with the multidisciplinary mentoring team provides a training platform designed to accomplish the following training goals: acquiring proficiency with 1) phenotypic characterization and the biological underpinnings of childhood psychopathology 2) the principles of bioinformatics and biostatistics as they apply to the design, conduct, and analysis of family-based association studies and 3) the technical and methodological issues related to methylation and gene expression analysis as they apply to psychiatric genetic research. Upon completion of the proposed project and the formal training described in the education plan, the candidate will have made significant progress towards initiating an independent academic career. PUBLIC HEALTH RELEVANCE: The children of women with mood or anxiety disorders ate at increased risk for the development of psychopathology. The examination of environmental and genetic predictors in prospectively- evaluated children will provide insight into the development of mental illness and will help to identify those requiring intervention.