Genomics of spermatogenic impairment

项目总结 这是对NICHD资助的男性不育遗传学倡议(Gemini)的续签申请 在R01HD078641下。在过去的资助期间，我们为我们对孟德尔式的理解增加了一些关键知识 非梗阻性无精子症(NOA)的形式。通过双子座，我们成功地驾驭了复杂的 建立和聘用有价值的临床合作者，超过招聘目标。此外，我们还有 开发并改进了强大的软件，以绘制n=1例NOA病例的遗传原因图，并在这样做的过程中 成功地发现了导致这种疾病的大量新的功能丧失变种。 描述严重生精障碍的潜在遗传基础是其关键 对提高生殖医学诊断和治疗水平的启示。提高对遗传基因的理解 男性不育的原因可能会对受影响男性的健康产生更广泛的影响。富饶 流行病学数据表明，男性不育是患其他合并症的危险因素，包括 各种类型的癌症、心血管疾病、糖尿病和总体健康状况都有所下降。虽然我们期待着 双子座将继续以不同的行动方法发现新的不孕突变，我们将统一我们的 围绕着“共病”这一中心主题展开了本轮研究。我们假设流行病学上的 男性不育与癌症等疾病之间的关联可能是由基因变异引起的 不育男性的生精障碍和突变负担增加。该计划的中心目标 该项目是继续识别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中的等位基因。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名正常男性新队列的测序 精液参数。借鉴双子座第一阶段的经验教训，我们提出了一些建议 对我们方法的补充，包括新的统计方法和对来自 案例，以及在复制和模式生物体研究方面的新合作。我们将应用分析工具 在R01HD078641下开发，从公开可用的基因组中识别潜在的不孕不育变异， 包括将通过英国生物库(UKBB)、Emerge Network和 犹他州基因组计划(UGP)。来自这些生物库的丰富表型资源将被用来执行这两项任务 全基因组关联研究(Phewas)和更有针对性的分析以确定 不孕不育以及已知的和新的并存。这些目标的成功实现将显著 加深对生精障碍的遗传基础和观察到的基础的理解 男性不育与其他合并症的关系，首要目标是改善男性 不孕不育的诊断和治疗，以及提高我们对不育男性进行风险分层的能力 在以后的生活中患上特定的合并症的可能性。

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.