Defining the multivariate genomic signature of pubertal markers and impact on lifespan psychopathology

项目摘要/摘要 青春期精神病理学在多个方面的增加对 这一时期的发病率、死亡率和幸福感，并为成年人的身心健康奠定了基础 困难。内在化精神病理学的患病率，女性平均较高，以及 外化的精神病理学，男性更高，在青春期分化，这一轨迹继续下去。 随之而来的是生命周期，暗示了性别分化机制。与此一致的是，一个稳健的 文献支持青春期时间(例如，开始)和青春期节奏(例如，变化率)的个体差异 作为精神病态增加的危险因素。然而，对单一性别具体指标的依赖，回溯性 报告，以及衡量这一动态成熟期的横断面数据都做出了确认 青春期的驱动机制和精神病理学很难联系在一起。目前的研究旨在利用 测量基因组学方法与两性的纵向数据相结合，以告知基因组信号 青春期通过多种生理和荷尔蒙指标，并检查青春期和 一生中的精神病态。第一个目标将利用基因组结构方程的新方法。 建模(基因组扫描电子显微镜；培训目标1)结合已发表的基因组相关统计数据 青春期时间(即月经初潮年龄、相对断音年龄、第一次面部相对年龄)的研究(GWAS) 毛发)、青春期生长、青春期成熟(即，晒黑阶段)、睾酮、雌二醇和性激素 结合球蛋白(SHBG)用于识别潜伏的青春期基因组因子，这些因子既是性别特有的，也是跨性别统一的。 从多变量青春期基因组因素得出的多基因得分(PGS；培训目标2)将得到验证 通过对纵向测量的青春期时间和节奏的样本外预测， 青春期大脑认知发育(ABCD)研究中的青春期标志物。第二个目标是调查 青春期多变量基因组信号与性别差异的遗传协方差测量 精神病理学(培训目标3)。这将通过(A)检查青春期和青春期之间的相关性来实现 成人精神病患者遗传结构的基因组因素模型和已建立的因素模型 使用基因组扫描电子显微镜的特征，并估计青春期PGS预测特定性别的终生精神疾病诊断 在英国生物库中；和(B)探索性别特定和性别统一的青春期PGS对纵向模拟的影响 ABCD研究中的青少年精神病理学症状，包括直接和纵向结合 测量青春期的时间和节奏。这项研究将产生一个全面的测量基因组模型。 青春期信号跨性别的多个相关表型，并提供改进的分析工具 遗传和非遗传来源的协变，以解开青春期风险的多层机制 精神变态学。

PROJECT SUMMARY/ABSTRACT Adolescent increases in psychopathology across multiple dimensions have a significant detrimental impact on morbidity, mortality and well-being during this period of life, and set the stage for adult physical and mental health difficulties. Prevalence rates of internalizing psychopathology, which is higher on average in females, and externalizing psychopathology, higher in males, diverge during adolescence, and this trajectory continues on subsequently over the lifespan, implicating sex-differentiated mechanisms. Consistent with this, a robust literature supports individual differences in pubertal timing (e.g., onset) and pubertal tempo (e.g., rate of change) as risk-factors for increased psychopathology. However, reliance on single sex-specific indicators, retrospective reports, and cross-sectional data to measure this dynamic period of maturation have made identification of mechanisms driving puberty and psychopathology links difficult. The current study aims to capitalize on measured genomics approaches integrated with longitudinal data in both sexes to inform the genomic signal of puberty across multiple physical and hormonal indicators, and examine genetic covariation between puberty and psychopathology across the lifespan. The first aim will leverage the novel method of genomic structural equation modeling (genomic SEM; training aim 1) to combine summary statistics from published genome-wise association studies (GWAS) of pubertal timing (i.e., age of menarche, relative age of voice break, relative age of first facial hair), pubertal growth spurt, pubertal maturation (i.e., Tanner staging), testosterone, estradiol, and sex hormone binding globulin (SHBG) to identify latent pubertal genomic factors both specific to and unified across sex. Polygenic scores (PGS; training aim 2) derived from the multivariate pubertal genomic factors will be validated by out-of-sample prediction of longitudinally measured pubertal timing and tempo characterized by multiple pubertal markers in the Adolescent Brain Cognitive Development (ABCD) Study. The second aim is to investigate measured genetic covariance of multivariate pubertal genomic signal with lifespan sex-differentiated psychopathology (training aim 3). This will be achieved through (a) examining correlations between the pubertal genomic factor model and previously established factor models of the genetic architecture of adult psychiatric traits using genomic SEM, and estimating pubertal PGS prediction of sex-specific lifetime psychiatric diagnoses in the UKBiobank; and (b) probing sex-specific and sex-unified pubertal PGS effects on longitudinally modeled adolescent symptoms of psychopathology in the ABCD Study, both directly and in conjunction with longitudinally measured pubertal timing and tempo. This research will yield a comprehensive model of measured genomic signal of puberty across multiple related phenotypes in both sexes, and provide improved tools for parsing genetic and non-genetic sources of covariation to disentangle multilayered mechanisms underlying pubertal risk for psychopathology.