Optimized Phenotypes for Genetic Association Studies

项目摘要 精神障碍是美国死亡和残疾的主要原因之一， 基因的影响。多基因风险评分（PRSs）的发展促进了我们对 精神疾病的病因和预测。然而，减贫战略在很大程度上是从个案中产生的， 诊断的对照研究。因此，PRS的预测效用受到诊断的影响。 不可靠性、疾病内异质性和诊断之间的定义重叠。这些问题限制 预测能力和遗传发现的特异性。这些问题可以使用经验， 可靠、同质和独特的三维表型。R21测试了这一点 通过推导PRS的诊断和经验表型开发的分层假设 精神病理学联盟的分类学，一个由100多名科学家组成的组织。全基因组关联研究 经验和诊断表型将在两个发现队列中进行（英国生物样本库，N= 500，000，和 费城神经发育队列，N= 10，000）。由此产生的PRS将在三个方面进行评估 重复组群（明尼苏达州双胞胎家庭研究，N= 8，900，追踪青少年个体生活研究， N= 2，200，青少年大脑认知发展研究，N= 10，600）。我们将测试HiTOP是否 PRS在功效和精确度方面优于诊断PRS，如（1）更大的遗传力和更低的遗传力。 多效性和（2）对靶表型和非靶表型的特异性的更大的预测能力。 该项目的成功将为未来的遗传研究带来更强大和更精确的目标。实证 表型可以扩展到大的遗传数据收集工作，提高精神病遗传学的效率。 研究，加快基因发现速度，加强遗传预测。

PROJECT SUMMARY Mental disorders are among the top causes of death and disability in the United States and are shaped by genetic influences. The development of polygenetic risk scores (PRSs) has advanced our understanding of both the etiology and prediction of mental illness. However, PRS have largely been generated from case- control studies of diagnoses. Consequently, the predictive utility of PRS has been affected by diagnostic unreliability, within-disorder heterogeneity, and definitional overlap among diagnoses. These problems limit predictive power and specificity of genetic findings. These problems may be addressed using empirical, dimensional phenotypes that are reliable, homogeneous, and distinct. This R21 proposes to test this hypothesis by deriving PRS for both diagnoses and empirical phenotypes developed by the Hierarchical Taxonomy of Psychopathology consortium, a group of over 100 scientists. Genome wide association studies of empirical and diagnostic phenotypes will be performed in two discovery cohorts (UK Biobank, N=500,000, and the Philadelphia Neurodevelopmental Cohort, N=10,000). The resulting PRS will be evaluated in three replication cohorts (Minnesota Twin Family Study, N=8,900, Tracking Adolescents’ Individual Lives Study, N=2,200, and the Adolescent Brain Cognitive Development study, N=10,600). We will test whether HiTOP PRS outperform diagnostic PRS in power and precision, as indexed by (1) greater heritability and lower pleiotropy and (2) greater predictive power for target phenotype and specificity from non-target phenotypes. Success of this project will result in more powerful and precise targets for future genetic research. Empirical phenotypes can be scaled to large genetic data collection efforts, improving the efficiency of psychiatric genetic research, accelerating the rate of gene discovery, and strengthening genetic prediction.