Identification and characterization of the molecular mechanisms underlying non-obstructive azoospermia by integrating genomic and transcriptomic data

Male infertility is a major health concern in today’s developed societies, as it affects 15% of couples of childbearing age. One of the most common and the most severe manifestation of male infertility is the non-obstructive azoospermia (NOA), which involves 10% of infertile men. This disease is characterized by the inability of the testis to produce sperm, and it is considered to be primarily associated with genetic factors. In this regard, different genetic aberrations, including microdeletions of the Y chromosome and karyotype abnormalities, have been directly involved in its development. However, these anomalies only explain around 15% of cases, with the remaining patients being classified as idiopathic. Consistent with this, candidate gene studies have provided clear evidences of a central role of common genetic variations, such as single nucleotide-polymorphisms, in the susceptibility to NOA, although they have been limited by reduced sample sizes in most cases. In relation to large-scale genetic studies, only two consistent genome-wide association studies (GWAS) have been published to date, both in Han Chinese populations without further replication in non-Asian cohorts. Complex diseases like NOA have a multifactorial aetiology that involves genetic, epigenetic, and environmental factors. During the last decade, thousands of robust genetic associations with complex diseases have been identified through the GWAS approach. Interestingly, most of the associated signals were located in non-coding regions of the genome, affecting the expression of the causative genes of the pathogenic phenotypes. In this context, the integration of both genomic and transcriptomic data have allowed a functional interpretation of the GWAS results, thus representing a significant progress in the understanding of the pathophysiology of many complex diseases. However, some diseases like NOA have not yet been fully benefited from the fast progress achieved by this type studies. Therefore, the main objective of this project is to conduct the first large-scale genetic study on male infertility due to NOA in a well-powered population of European ancestry.
Specifically, we aim to perform a GWAS in a population of 700 NOA patients and 1,000 healthy men from Spain, and to integrate the results with expression data obtained from whole transcriptome sequencing of testis biopsies from 50 GWAS-typed individuals. In addition, we will carry out a functional annotation of the results using different public databases and state-of-the-art bioinformatics tools, in order to elucidate the main causal genes and molecular pathways underlying the disease. Finally, we will evaluate the possible application of our data for the development of potential biomarkers for diagnosis and prognosis of the real possibilities of NOA patients to father a biological child through assisted reproductive techniques. In particular, we will investigate the possible relationship of the associated genetic markers with the probability of sperm retrieval through testicular sperm extraction (TESE), the cumulative probability of pregnancy per cycle of intracytoplasmic sperm injection (ICSI), and the live birth rate of these patients. Based on the above, we strongly believe that the proposed study will imply a clear socio-economic impact that could benefit thousands of couples that are unable to conceive due to male infertility issues, thus helping to address one of the major challenges of the society