GENNAPREL - Genetic rElationships betweeN NauseA symPtoms and pREgnancy Loss

Abstract:

Women’s reproductive health remains one of the least systematically studied areas despite its critical importance to individuals and society. With the aging population across Europe and the rising age at conception, fertility problems, including miscarriages and recurrent pregnancy loss (RPL), are becoming increasingly common. Although assisted reproductive technologies such as in-vitro fertilization are more widely used, challenges related to pregnancy loss persist. Currently, genetic studies on miscarriage are very limited, especially in underrepresented populations like Eastern Europeans, highlighting the urgent need for large-scale investigations.

Symptoms such as nausea and vomiting affect approximately 70% of pregnant women, predominantly in the first trimester, often impacting quality of life and occasionally signaling pregnancy loss. While hereditary factors have been implicated in both RPL and nausea, their genetic bases and the overlap between these traits remain poorly understood. This project aims to fill these gaps by exploring the genetic architecture of nausea and pregnancy loss and elucidating their shared and distinct biological pathways through comprehensive genome-wide analyses.

Using data from the UK Biobank and the unique Ukrainian cohort, among other European datasets, the project will perform large-scale genome-wide association studies (GWAS), including multi-phenotype GWAS, to identify genetic variants influencing susceptibility to nausea, idiopathic pregnancy loss, and related conditions. Causal relationships between these phenotypes will be investigated using bi-directional Mendelian randomization. Furthermore, the study will identify rare coding mutations associated with extreme recurrent pregnancy loss and develop ethnicity-specific polygenic risk scores to predict individual genetic risk, with a focus on Eastern European populations.

This research will advance understanding of the complex genetics underlying women’s reproductive health, uncover novel candidate genes and biological pathways, and provide valuable tools for genetic risk prediction. The results are expected to improve early identification of women at risk for pregnancy loss, potentially guiding personalized clinical interventions and contributing to better reproductive healthcare.

Expected Results

• Identification of novel genetic loci associated with nausea symptoms and recurrent pregnancy loss through single-trait and multi-phenotype GWAS.
• Clarification of causal relationships between nausea, pregnancy loss, and related traits via Mendelian randomization analyses.
• Discovery of rare coding mutations linked to extreme recurrent pregnancy loss, providing new insights into the molecular mechanisms involved.
• Development and validation of ethnicity-specific polygenic risk scores that accurately predict genetic predisposition to pregnancy loss, particularly in Eastern European populations.
• Generation of a comprehensive genetic resource integrating common and rare variant data for reproductive health traits, facilitating future research and clinical applications.
• Strengthening of international research collaborations and enhancement of multidisciplinary expertise in genomics, epidemiology, and bioinformatics.