Genetic and molecular basis of severe spermatogenic failure

Male infertility represents one of the major health challenges in today’s developed societies, since it affects 15% of couples of childbearing age. One of its most common manifestations, and the most serious, is non-obstructive azoospermia (NOA), responsible for 10% of infertility cases in men. NOA is characterized by the inability of the testicle to produce sperm. Another cause of male infertility slightly less severe than NOA is severe oligozoospermia (SO), which is defined as a reduction in the number of sperm per milliliter in the ejaculate. Men who present between 1-5 million sperm per ml are classified in this group. Both conditions are caused primarily by failures in the spermatogenic process, and are mainly associated with genetic factors. However, the genetic abnormalities found in these patients only explain about 25% of the cases, the infertility of the remaining patients being considered idiopathic. Although the etiology of this idiopathic form of infertility remains unknown, there is ample evidence indicating that this condition has an important genetic component that influences its susceptibility and development, especially common genome variation such as single nucleotide polymorphisms (SNPs) or copy number variations (CNVs). This evidence has been obtained from candidate gene studies to a large extent, with a few large-scale genetic studies conducted in very small populations or of Asian origin. In the last decade, mainly due to genome-wide association studies (GWAS), thousands of firm genetic associations with diseases of complex etiology have been established. In addition, the rise of public omics databases, as well as the development of powerful bioinformatics tools, has made it possible to give a functional interpretation to GWAS results and to advance considerably in the understanding of the pathophysiology of many complex diseases. However, there are diseases that have not yet been able to fully benefit from the progress produced by this type of studies in recent years, as is the case of male infertility due to NOA and OS. For this reason, the main objective of the study in which this project is framed is to carry out a large-scale genetic analysis in a large population of infertile men of European origin. To this end, we intend to genotype in a novel GWAS platform a total of 1350 patients diagnosed with severe spermatogenic failure (including 450 NOA and 900 SO) and 400 controls of European origin (Spain, Germany and Portugal). The data generated will be analyzed together with another GWAS dataset of 550 cases (500 NOA and 50 SO) and 1050 Spanish and Portuguese controls that we already have in our laboratory, in order to carry out a study of high statistical power that will allow us to identify the main genes and molecular pathways involved in male infertility. Additionally, we will study the possible functional implications of the described associations by in silico and in vitro studies. Finally, we will evaluate the possible application of the results obtained in the development of possible diagnostic and prognostic biomarkers, which may be useful to improve genetic counseling to patients who require it, as well as to provide reliable indicators of the possible success or failure in the recovery of viable spermatozoa in testicular biopsies of AON patients. Due to the above, we consider that this project would have a great socioeconomic impact and would help to address one of the main challenges of society.