Genomics of spermatogenic impairment

项目概要 这是对 NICHD 资助的男性不育遗传学计划 (GEMINI) 的更新申请 下 R01HD078641。在过去的资助期间，我们增加了对孟德尔的理解的关键知识 各种形式的非梗阻性无精症（NOA）。通过 GEMINI，我们成功地解决了错综复杂的问题 建立和吸引有价值的临床合作者，超越招募目标。此外，我们还有 开发和完善了强大的软件来绘制 n=1 例 NOA 的遗传原因，并以此为基础 成功鉴定出大量导致该疾病的新型功能丧失变异。 严重生精障碍的潜在遗传基础的表征对于其发生至关重要 对改善生殖医学诊断和治疗的影响。加深对遗传的理解 男性不育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，包括 各种癌症、心血管疾病、糖尿病和整体健康状况下降。虽然我们期待 GEMINI将继续以多样化的行动方法发现新的不孕不育突变，我们将统一我们的 本周期的研究围绕“共病”这一中心主题。我们假设流行病学 男性不育症与癌症等疾病之间的关联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。该组织的中心目标是 该项目的目的是继续识别新的孟德尔形式的严重生精障碍和其他 已知和可疑的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 对 1000 名患有严重生精障碍的男性和 1000 名正常男性的新队列进行测序 精液参数。借鉴 GEMINI 第一阶段的经验教训，我们提出了一些建议 我们的方法的补充，包括新的统计方法和原代组织的功能测定 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 根据 R01HD078641 开发，用于从公开可用的基因组中识别潜在的不育变异， 其中包括超过 500,000 个可通过英国生物银行 (UKBB)、eMERGE 网络和 犹他州基因组计划（UGP）。这些生物库丰富的表型资源将用于执行 全表组关联研究 (PheWAS) 和更有针对性的分析，以确定之间的遗传联系 不孕症以及已知和新的合并症。这些目标的成功完成将显着 提高我们对生精障碍的遗传基础和观察到的基础的理解 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 不育症的诊断和治疗，以及提高我们根据不育症男性的情况对不育症男性进行风险分层的能力 在以后的生活中出现特定合并症的可能性。

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.