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.

项目总结/摘要 青少年在多个维度上精神病理学的增加对以下方面有显著的不利影响： 发病率，死亡率和福祉在这一时期的生活，并为成年人的身心健康奠定了基础 困难内化精神病理学的发病率，女性平均较高， 外化的精神病理学，在男性中更高，在青春期出现分歧，这种轨迹继续下去， 随后在整个生命周期中，暗示性别分化机制。与此相一致，一个强大的 文献支持青春期时间的个体差异（例如，开始）和青春期节奏（例如，变化率） 作为精神病理学增加的风险因素。然而，依赖单一性别指标， 报告和横截面数据，以衡量这一动态的成熟期已经确定， 驱动青春期的机制和精神病理学联系困难。目前的研究旨在利用 测量的基因组学方法与两种性别的纵向数据相结合， 青春期在多个物理和激素指标，并检查青春期和 精神病理学的影响第一个目标将利用基因组结构方程的新方法 建模（基因组SEM;训练目标1）以结合来自已发表的基因组关联的联合收割机汇总统计 青春期时间的研究（GWAS）（即，初潮年龄，相对变声年龄，相对第一面部年龄 毛发），青春期生长突增，青春期成熟（即，坦纳分期）、睾酮、雌二醇和性激素 结合球蛋白（SHBG），以确定潜在的青春期基因组因素，既具体和统一跨性别。 将验证来自多变量青春期基因组因素的多基因评分（PGS;训练目标2） 通过纵向测量的青春期时间和节奏的样本外预测， 青春期标记物在青少年大脑认知发展（ABCD）研究。第二个目的是调查 具有寿命性别分化的多变量青春期基因组信号的测量遗传协方差 心理病理学（培训目标3）。这将通过以下方式实现：（a）检查青春期 基因组因素模型和先前建立的成人精神病遗传结构的因素模型 使用基因组扫描电镜特征，并估计青春期PGS预测性别特异性终身精神病诊断 和（B）探索性别特异性和性别统一的青春期PGS对纵向建模的 在ABCD研究中，青少年的精神病理学症状，无论是直接还是纵向 测量青春期的时间和节奏这项研究将产生一个全面的模型，测量基因组 在两种性别中跨多个相关表型青春期信号，并提供用于解析的改进工具 共变的遗传和非遗传来源，以解开青春期风险的多层机制 精神病理学