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性的，但一项新兴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障碍。然而，遗传学以及母亲的压力，抑郁和焦虑影响儿童行为的途径仍然不清楚。利用一项实验室可用的、无偏倚的全基因组关联研究（GWAS），我们确定了与ADHD儿童的儿童行为问题、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，可能会改变后代的脆弱性，以后的精神病理学和遗传变异将增加后代的风险发展儿童精神病理学。该假设将通过检查以下相关性进行检验：1）基于证据的候选基因多态性与前瞻性评估的表型，妊娠期间患有精神疾病的女性所生的高风险儿童; 2）胎盘组织中这些候选基因的甲基化模式与这些儿童中测量的性状和行为; 3）胎盘组织中这些基因编码的mRNA表达。 本研究提案沿着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）儿童精神病理学的表型特征和生物学基础2）生物信息学和生物统计学的原理，因为它们适用于设计，进行，和分析的家庭为基础的关联研究和3）的技术和方法学问题，甲基化和基因表达分析，因为它们适用于精神病遗传学研究。在完成拟议的项目和教育计划中所述的正式培训后，候选人将在开始独立的学术生涯方面取得重大进展。 公共卫生相关性：患有情绪障碍或焦虑症的妇女的孩子进食增加了精神病理学发展的风险。在前瞻性评估的儿童中检查环境和遗传预测因子将提供对精神疾病发展的深入了解，并将有助于确定那些需要干预的儿童。

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.