Genomics of spermatogenic impairment

生精障碍的基因组学

• 批准号: 10706967
• 负责人: Kenneth Ivan Aston
• 金额: $ 62.27万
• 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/10706967
• 关键词: Affect; Alleles; Architecture; Biological Assay; Biological Models; Cardiovascular Diseases; Caring; Chromosome Mapping; 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; Heterozygote; Impairment; Infertility; International; Knowledge; Learning; Life; Link; Male Infertility; Malignant Neoplasms; 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; biobank; cancer type; causal variant; cohort; comorbidity; epidemiologic data; exome sequencing; genetic architecture; genetic information; genetic variant; improved; loss of function; men; model organism; 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 这是建立的男性不育症倡议（Gemini）的NICHD资助的遗传学的续订应用 根据R01HD078641。在过去的资金期间，我们添加了关键知识，以理解门德利安 非目标化植物植物（NOA）的形式。通过双子座，我们成功地导航了复杂性 建立和引人入胜的有价值的临床合作者，超出了招聘目标。此外，我们还有 开发和完善了功能强大的软件，以绘制n = 1个NOA案例的遗传原因，因此有 成功地确定了大量负责该疾病的新型功能丧失变体。 对严重精子损伤的基础遗传基础的表征对于其 改善生殖医学诊断和治疗的实施。改善对遗传的理解 男性不育症的原因可能对受影响男性的健康具有更大的影响。丰富 流行病学数据表明，男性不孕症是发展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降低。当我们期望 那个双子座将继续以潜水员的行动方法来揭示新的不育突变，我们将统一我们的 在此周期中研究“合并症”的中心主题。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依据的变异引起的 生理性障碍和不育男性突变的燃烧增加。核心目标 项目将继续识别新的门德利形式的严重精子障碍和额外 已知和怀疑的男性不育症基因的等位基因。这个遗传发现将由外显子驱动 对1000名患有严重精子障碍和1000名正常男性的1000名男性的新队列的测序 精液参数。利用双子座第一阶段的课程，我们提出了许多 在我们的方法中的补充，包括新的统计方法和功能测定。 案例以及复制和模型有机体研究的新合作。我们将应用分析工具 根据R01HD078641开发，以确定公开可用基因组的潜在不孕变异， 包括500,000多个将通过英国生物银行（UKBB），Emerge Network和 犹他州基因组项目（UGP）。这些生物库中丰富的表型资源将使用 全球范围的关联研究（PHEWAS）和更多针对性的分析，以识别遗传联系 不孕症以及已知和新颖的合并症。这些目标成功完成将显着 提高我们对精子障碍的遗传基础的理解和观察到的基础 男性不育症与其他合并症之间的关系，以及改善男性的总体目标 不育诊断和治疗，以及根据他们的风险分层男性的能力 以后生活中发展特定合并症的可能性。

项目成果

A de novo paradigm for male infertility.

• DOI: 10.1038/s41467-021-27132-8
• 发表时间: 2022-01-10
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Oud MS;Smits RM;Smith HE;Mastrorosa FK;Holt GS;Houston BJ;de Vries PF;Alobaidi BKS;Batty LE;Ismail H;Greenwood J;Sheth H;Mikulasova A;Astuti GDN;Gilissen C;McEleny K;Turner H;Coxhead J;Cockell S;Braat DDM;Fleischer K;D'Hauwers KWM;Schaafsma E;Genetics of Male Infertility Initiative (GEMINI) consortium;Nagirnaja L;Conrad DF;Friedrich C;Kliesch S;Aston KI;Riera-Escamilla A;Krausz C;Gonzaga-Jauregui C;Santibanez-Koref M;Elliott DJ;Vissers LELM;Tüttelmann F;O'Bryan MK;Ramos L;Xavier MJ;van der Heijden GW;Veltman JA
• 通讯作者: Veltman JA

The piRNA-pathway factor FKBP6 is essential for spermatogenesis but dispensable for control of meiotic LINE-1 expression in humans.

• DOI: 10.1016/j.ajhg.2022.09.002
• 发表时间: 2022-10-06
• 期刊: American journal of human genetics
• 影响因子: 9.8