Genomics of spermatogenic impairment

生精障碍的基因组学

• 批准号: 10367725
• 负责人: Kenneth Ivan Aston
• 金额: $ 63.52万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-10 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10367725
• 关键词: Affect; Alleles; Animal Model; Architecture; Biological Assay; Biological Models; Cardiovascular Diseases; Caring; Clinical; Collaborations; Complex; Computer software; Diabetes Mellitus; Diagnosis; Disease; Electronic Medical Records and Genomics Network; Epidemiology; Etiology; Experimental Designs; Funding; Generations; Genes; Genetic; Genome; Genomics; Goals; Health; Impairment; Infertility; International; Knowledge; Life; Link; Male Infertility; Malignant Neoplasms; Maps; Methods; Modeling; Molecular; Morphology; Multicenter Studies; Mutation; National Institute of Child Health and Human Development; Patients; Phase; Phenotype; Prevalence; Productivity; Reproductive Medicine; Research; Resources; Risk; Risk Factors; Role; Seminal fluid; Statistical Methods; Testicular Tissue; Testing; Testis; Tissues; United States National Institutes of Health; Utah; Validation; Variant; Work; Zebrafish; analytical tool; base; biobank; cancer type; causal variant; cohort; comorbidity; epidemiologic data; exome sequencing; genetic architecture; genetic information; genetic variant; improved; loss of function; men; novel; personalized genomic medicine; phenome; recruit; risk stratification; single-cell RNA sequencing; sperm cell; tool

PROJECT SUMMARY This is a renewal application to the NICHD-funded Genetics of Male Infertility Initiative (GEMINI) established under R01HD078641. In the past funding period, we added key knowledge to our understanding of Mendelian forms of nonobstructive azoospermia (NOA). Through GEMINI, we have successfully navigated the intricacies of establishing and engaging valuable clinical collaborators, exceeding recruitment goals. In addition, we have developed and refined powerful software to map genetic causes for n=1 cases of NOA, and in so doing have successfully identified a large number of novel loss-of-function variants responsible for the disease. Characterization of the underlying genetic basis for severe spermatogenic impairment is critical for its implications in improving diagnosis and treatment in reproductive medicine. Improved understanding of genetic causes of male infertility may have broader implications for the health of affected men. Abundant epidemiological data indicate that male infertility is a risk factor of developing other comorbidities including various types of cancer, cardiovascular disease, diabetes and overall reduced general health. While we expect that GEMINI will continue to uncover new infertility mutations with diverse methods of action, we will unify our research in this cycle around the central theme of “comorbidity”. We hypothesize that the epidemiological association between male infertility and diseases such as cancer may be caused by variants underlying spermatogenic impairment and the increased burden of mutations in infertile men. The central goal of the project is to continue to identify new Mendelian forms of severe spermatogenic impairment and additional alleles in known and suspected male infertility genes. This genetic discovery will be driven by exome sequencing of a new cohort of 1000 men with severe spermatogenic impairment and 1000 men with normal semen parameters. Drawing upon lessons from the first phase of GEMINI, we are proposing a number of additions to our approach, including new statistical methods and functional assays of primary tissue from cases, and new collaborations for replication and model organism studies. We will apply the analytical tools developed under R01HD078641 to identify potential infertility variants from publicly available genomes, including over 500,000 that will be available through the UK Biobank (UKBB), the eMERGE Network, and the Utah Genome Project (UGP). The rich phenotypic resources from these biobanks will be used to perform both phenome-wide association studies (PheWAS) and more targeted analyses to identify genetic links between infertility and both known and novel comorbidities. Successful completion of these aims will significantly improve our understanding of the genetic basis for spermatogenic impairment and the basis for the observed relationship between male infertility and other comorbidities, with the overarching goals of improving male infertility diagnosis and treatment as well as improving our capacity to risk-stratify infertile men based on their likelihood of developing specific comorbidities later in life.

项目摘要 这是对NICHD资助的男性不育症遗传学倡议（GEMINI）的更新申请， 根据R01HD078641。在过去的资助期间，我们增加了我们对孟德尔的理解的关键知识， 非梗阻性无精子症（NOA）通过双子座，我们成功地驾驭了 建立和吸引有价值的临床合作者，超过招募目标。另外我们有 开发并完善了强大的软件，以绘制n=1例NOA的遗传原因，并在此过程中， 成功地鉴定了大量导致该疾病的新型功能丧失变体。 严重生精障碍的潜在遗传基础的特征对于其治疗至关重要。 对改善生殖医学诊断和治疗的意义。更好地理解遗传 男性不育症的原因可能对受影响男性的健康产生更广泛的影响。丰富 流行病学数据表明，男性不育是发生其他合并症的危险因素， 各种类型的癌症、心血管疾病、糖尿病和总体健康状况的下降。虽然我们预计 GEMINI将继续以不同的行动方法发现新的不育突变，我们将统一我们的 本周期的研究围绕“科摩罗”这一中心主题。我们假设流行病学 男性不育与癌症等疾病之间的联系可能是由潜在的变异引起的。 不育男性的生精障碍和突变负担增加。的中心目标 该项目的目的是继续确定新的孟德尔形式的严重生精障碍和其他 已知和疑似男性不育基因的等位基因。这一基因发现将由外显子组驱动 1000名严重生精障碍男性和1000名正常男性的新队列测序 精液参数根据GEMINI第一阶段的经验教训，我们提出了一些建议， 增加我们的方法，包括新的统计方法和功能测定的主要组织从 案例，以及复制和模式生物研究的新合作。我们将应用分析工具 在R01HD 078641下开发，以从公开可用的基因组中鉴定潜在的不育变体， 包括将通过英国生物库（UKBB），eMERGE网络和 犹他州基因组计划。这些生物库中丰富的表型资源将用于执行这两项任务 全表型关联研究（PheWAS）和更有针对性的分析，以确定 不孕症以及已知和新的合并症。这些目标的成功实现将大大 提高我们对生精障碍的遗传基础和观察到的 男性不育症与其他合并症之间的关系，总体目标是改善男性不育症 不孕症的诊断和治疗，以及提高我们的能力，根据他们的风险分层不育男性， 在以后的生活中发生特定合并症的可能性。