Characterizing the genetic etiology of delayed puberty with integrative genomic techniques

利用综合基因组技术表征青春期延迟的遗传病因

基本信息

批准号：
10663605
负责人：
Xuefang Zhao
金额：
$ 13.59万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-02 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10663605
关键词：
Address Adult Advisory Committees Affect Age Anxiety Area Award Bayesian Modeling Biological Categories Cell Line Cell model Child Clinical Code Collection Committee Members Constitution Constitutional Data Data Set Delayed Puberty Disease Endocrine Endocrinologist Engineering Ensure Etiology Failure Feedback Foundations Gene Expression Gene Frequency General Hospitals Genes Genetic Genetic Diseases Genetic Predisposition to Disease Genetic Variation Genome Genomic medicine Genomics Gonadotropin Hormone Releasing Hormone Hormone secretion Human Genome Hypogonadism Idiopathic Hypogonadotropic Hypogonadism Individual Infertility Joints Kallmann Syndrome Knowledge acquisition Lead Leadership Learning Massachusetts Medicine Mental Depression Mentors Methods Mutation Neurons Pathogenicity Pathway Analysis Pathway interactions Patients Phase Phenotype Population Positioning Attribute Postdoctoral Fellow Process Puberty RNA Sequences Refractory Regulation Regulatory Element Repetitive Sequence Reproductive Biology Reproductive Endocrinology Research Research Personnel Resources Risk Risk Factors Sampling Single Nucleotide Polymorphism Social isolation Solid Statistical Methods Statistical Models Techniques Training Untranslated RNA Variant aggregation database biobank career career development case control causal variant cohort collaborative environment de novo mutation differential expression disease phenotype exome sequencing functional genomics gene discovery gene network genetic pedigree genetic variant genome sequencing genomic data genomic locus genomic variation innovation insertion/deletion mutation insight loss of function mutation machine learning model medical schools novel phenotypic data post-doctoral training prevent proband professor programs psychologic rare condition reproductive reproductive system disorder research faculty risk variant skills success tool training opportunity transcriptome transcriptome sequencing transmission process whole genome

项目摘要

Idiopathic hypogonadotropic hypogonadism (IHH) and Kallmann syndrome (KS) are rare congenital forms of infertility that prevent patients from entering puberty and lead to infertility in their adulthood, thus causing significant burden to affected children both physically and psychologically. The lack of gonadotrophin-releasing hormone (GnRH), the hormone secreted by GnRH neurons, is the cause of IHH and KS. Despite previous efforts to identify causal variants in IHH/KS through pedigree analyses and studies to explore the functional dysregulation in GnRH neurons, the genetic etiology of IHH/KS remains largely unexplained. To address this challenge, I will (1) define a complete spectrum of genomic variants, ranging from single nucleotide variants (SNVs) to large structural variation (SV), from whole genome sequencing (WGS) of the largest IHH/KS cohort assembled worldwide, and perform joint association of coding and non-coding variants using already established statistical methods to identify risk genes and regulatory elements; (2) examine the impact of loss of function (LoF) mutations of infertility associated genes on transcriptome dysregulation in GnRH neurons; and (3) examine the effect of genomic variants in a broader range of individuals affected by constitutional delayed puberty (CDP). The planned research incorporates statistical modeling of genomic variants in trio genomes and interpretation of transcriptome dysregulation from RNA sequences in GnRH neurons to gain insights into the genetic etiology of rare congenital infertility. To ensure success of the project, Dr. Michael Talkowski, Director of the Center for Genomic Medicine (CGM) at Mass General Hospital (MGH), Harvard Medical School (HMS) and the Broad Institute, will serve as the primary mentor. Drs. Stephanie Seminara, reproductive endocrinologist and Professor of Medicine at MGH and HMS, and Harrison Brand, Assistant Professor and Lead of the Broad SV Team, will provide additional guidance as co-mentors. Drs. Talkowski and Seminara are world leaders in computational genetics and reproductive biology, and Dr. Brand has led numerous studies interpreting SVs in disease genomes and recently successfully transitioned to an independent research faculty at MGH and HMS through a K99/R00 award. In addition to their complementary leadership, a team of advisory committee members at various career stages will provide scientific feedback and career development advice throughout the project. The abundance of resources, tools, and scientific and clinical expertise accessible through the CGM, MGH, and the Broad Institute form a highly collaborative environment ideally positioned to support my transition to independence. The research will extend my expertise to include cutting-edge techniques and provide the opportunity to learn about phenotypes associated with congenital and constitutional infertility disorders, how to apply statistical methods to identify causal genomic loci, and how to interpret deviations in transcriptome activity. With these skills, I will be able to functionally characterize genetic variation affecting reproductive disorders and be well- positioned to launch my own high-performing and innovative independent research program.

特发性低促性腺激素性性腺功能减退症 (IHH) 和卡尔曼综合征 (KS) 是罕见的先天性性腺功能减退症不孕症阻止患者进入青春期并导致成年后不孕，从而导致给受影响的儿童带来身体和心理上的巨大负担。缺乏促性腺激素释放激素 (GnRH) 是 GnRH 神经元分泌的激素，是 IHH 和 KS 的病因。尽管之前的努力通过谱系分析和研究来识别 IHH/KS 的因果变异，以探索功能性变异由于 GnRH 神经元失调，IHH/KS 的遗传病因在很大程度上仍无法解释。为了解决这个问题挑战，我将 (1) 定义完整的基因组变异谱，范围从单核苷酸变异 (SNV) 到大结构变异 (SV)，来自最大的 IHH/KS 队列的全基因组测序 (WGS) 在全球范围内组装，并使用已经建立的编码和非编码变体进行联合关联识别风险基因和调控元件的统计方法； (2)检查功能丧失的影响 (LoF) 不孕相关基因突变导致 GnRH 神经元转录组失调； (3) 检查基因组变异对更广泛的受体质性青春期延迟（CDP）影响的个体的影响。计划中的研究结合了三重基因组中基因组变异的统计模型和解释 GnRH 神经元 RNA 序列的转录组失调，以深入了解 GnRH 神经元的遗传病因学罕见先天性不孕症。为了确保该项目的成功，该中心主任 Michael Talkowski 博士麻省总医院 (MGH)、哈佛医学院 (HMS) 和 Broad 医学院的基因组医学 (CGM) 学院，将担任主要导师。博士。 Stephanie Seminara，生殖内分泌学家兼教授 MGH 和 HMS 医学博士和助理教授兼 Broad SV 团队负责人 Harrison Brand 将作为共同导师提供额外指导。博士。 Talkowski 和 Seminara 是计算领域的世界领导者遗传学和生殖生物学，布兰德博士领导了许多解释疾病基因组中的 SV 的研究最近通过 K99/R00 成功转型为 MGH 和 HMS 的独立研究人员奖。除了互补的领导力之外，咨询委员会成员组成的团队来自不同的职业领域。阶段将在整个项目中提供科学反馈和职业发展建议。丰富度可通过 CGM、MGH 和 Broad Institute 获取资源、工具以及科学和临床专业知识形成一个高度协作的环境，非常适合支持我向独立过渡。该研究将扩展我的专业知识，包括尖端技术并提供学习的机会关于与先天性和体质性不孕症相关的表型，如何应用统计识别因果基因组位点的方法，以及如何解释转录组活性的偏差。有了这些技能，我将能够从功能上描述影响生殖障碍的遗传变异，并保持健康- 定位于启动我自己的高性能和创新的独立研究项目。