Integrated analysis of genetic and epigenetic variants in central precocious puberty

摘要： 下丘脑-垂体-性腺（HPG）轴调节青春期开始的时间。过早再激活 儿童期促性腺激素释放激素（GnRH）分泌减少导致中枢性早熟 青春期（CPP）。CPP，除了赋予行为和精神障碍，还与增加 成年期心血管和心脏代谢疾病、肥胖、糖尿病和癌症的风险。因此 迫切需要确定参与HPG轴早期再激活的途径，以更好地诊断 治疗这种疾病研究已经确定了KISS 1和KISS 1 R在HPG激活中的核心作用 轴线最近，我们在家族性CPP中发现了印记基因MKRN 3和DLK 1的突变， 这表明遗传和表观遗传的改变都在调节青春期的时间。我们现在建议使用一个 群体遗传学方法进行遗传和表观遗传变异的综合分析，以确定新的 在没有已知原因的个体中CPP的潜在原因。本研究的目的是探讨 特发性CPP患者拷贝数变异与DNA甲基化之间的关系我们将解决 本研究的目的有两个：1）进行遗传变异和DNA甲基化之间的关联分析， CPP患者队列;以及2）使用第二患者队列验证所识别的相关性，以及 进一步确定与DNA甲基化相关的区域是否富集了所定义的调控元件， Encyclopedia of DNA Elements（ENCODE）这一拟议的分析将有助于界定 相关的遗传和表观遗传改变的基础CPP。研究结果将有助于开发新的 CPP的诊断策略，并促进及时干预和治疗，以改善健康和质量 这些孩子的生活。

Abstract: The hypothalamic-pituitary-gonadal (HPG) axis regulates the timing of pubertal onset. Premature re-activation of gonadotropin-releasing hormone (GnRH) secretion in childhood leads to development of central precocious puberty (CPP). CPP, in addition to conferring behavioral and psychiatric disorders, is associated with increased risk of cardiovascular and cardiometabolic disease, obesity, diabetes, and cancer in adulthood. Therefore, there is a dire need to identify the pathways that are involved in early re-activation of the HPG axis to better diagnose and treat this disorder. Studies have identified the central roles of KISS1 and KISS1R in activation of the HPG axis. More recently, we have identified mutations in the imprinted genes, MKRN3 and DLK1, in familial CPP, suggesting that both genetic and epigenetic alterations regulate the timing of puberty. We now propose to use a population genetics approach to perform an integrated analysis of genetic and epigenetic variants to identify new underlying causes for CPP in individuals with no known causes. The objective of our study is to investigate the association between copy number variants and DNA methylation in patients with idiopathic CPP. We will address this objective in two aims: 1) perform association analysis between genetic alterations and DNA methylation in a cohort of patients with CPP; and 2) validate the associations identified using a second cohort of patients and further determine if the regions associated with DNA methylation are enriched for regulatory elements as defined by the Encyclopedia of DNA Elements (ENCODE) consortium. This proposed analysis will help to delineate correlated genetic and epigenetic alterations underlying CPP. The results will aid in the development of new diagnostic strategies for CPP and facilitate timely intervention and treatment to improve the health and quality of life for these children.