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

定义青春期标记的多变量基因组特征及其对寿命精神病理学的影响

• 批准号: 10641312
• 负责人: Megan Wales Patterson
• 金额: $ 16.97万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10641312
• 关键词: Adolescence; Adolescent; Adult; Age; Architecture; Automobile Driving; Behavioral; Brain; Childhood; Complex; Data; Development; Dimensions; Equation; Estradiol; Event; Face; Female; Genetic; Genetic Models; Genome; Genomic approach; Genomics; Genotype; Grain; Growth; Hair; Health; Hormonal; Human; Individual Differences; Life; Life Cycle Stages; Link; Literature; Longevity; Longitudinal Studies; Measures; Menarche; Mental Depression; Mental Health; Mental disorders; Methods; Modeling; Morbidity - disease rate; Nature; Outcome; Pathway interactions; Personal Satisfaction; Phenotype; Prevalence; Psychiatric Diagnosis; Psychopathology; Puberty; Publishing; Reporting; Research; Research Personnel; Risk; Risk Factors; Risk Taking; Sampling; Sex Differences; Sex Differentiation; Sex Hormone-Binding Globulin; Signal Transduction; Site; Source; Staging; Structure; Symptoms; Testosterone; Time; Training; Variant; Voice; Youth; cognitive development; early adolescence; genetic architecture; genetic association; genome wide association study; genomic locus; genomic signature; improved; insight; male; mortality; non-genetic; novel; physical conditioning; psychiatric symptom; pubertal timing; rate of change; sex; sexual dimorphism; statistics; tool; trait

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.

项目摘要/摘要 跨多个维度的心理病理学的青春期增加对 在这一生活期间的发病率，死亡率和福祉，并为成人身心健康奠定了基础 困难。内部心理病理学的患病率，女性平均而言较高，并且 心理病理学外部化，男性较高，青春期差异，这种轨迹仍在继续 随后在整个寿命中，暗示了性别差异的机制。与此一致，一个强大的 文献支持青春期时机（例如发作）和青春期节奏的个体差异（例如，变化速度） 作为增加心理病理学的风险因素。但是，依赖单个性别的指标，回顾性 报告和横截面数据以衡量这个动态的成熟时期已确定 驱动青春期和心理病理学的机制困难。当前的研究旨在利用 测量的基因组学方法与两个性别中的纵向数据集成在一起，以告知基因组信号 跨多个物理和荷尔蒙指标的青春期，并检查青春期和 整个生命周期的心理病理学。第一个目标将利用新颖的基因组结构方程方法 建模（基因组SEM；培训目标1）结合了已发表的基因组协会的汇总统计数据 青春期时机的研究（GWAS）（即初潮的年龄，相对年龄，声音中断的年龄，第一面部面部的相对年龄 头发），青春期生长突破，青春期成熟（即制革商舞台），睾丸激素，雌二醇和性激素 结合球蛋白（SHBG）以识别特有和统一性别的潜在青春期基因组因子。 从多元青春期基因组因子得出的多基因分数（PGS；训练目标2）将得到验证 通过样本外预测的纵向测量的青春期时间和节奏，其特征是多个 青少年脑认知发展（ABCD）研究中的青春期标记。第二个目的是调查 多变量青春期基因组信号的遗传协方差，寿命分化 精神病理学（培训目标3）。这将通过（a）检查青春期之间的相关性来实现 基因组因子模型和先前确定的成人精神病遗传结构的因子模型 使用基因组SEM的特征，并估算青春期PGS性别特异性终生诊断的预测 在UKBiobank； （b）探测性别特异性和性别统一的青春期PGS对纵向建模的影响 在ABCD研究中，精神病学的青少年症状直接并与纵向结合 测量的青春期时间和节奏。这项研究将产生一个测量基因组的全面模型 两个性别中多种相关表型的青春期信号，并提供改进的解析工具 协方差的遗传和非遗传来源，以消除青春期风险的多层机制 用于心理病理学。