Qi Guo ^1* Kristina Allen-Brady ² Marta Olszewska ³

• ¹ Insmed Innovation UK,, Cambridge, United Kingdom
• ² The University of Utah, Salt Lake City, Utah, United States
• ³ Polish Academy of Sciences, Warsaw, Masovian, Poland

The research topic "Women in Genetic Epidemiology" highlights the contributions of women scientists who are advancing the field of genetic epidemiology through diverse research efforts. This collection of papers not only showcases new developments and innovative work led by women across various disciplines within genetic epidemiology but also underscores the importance of gender diversity in driving scientific discovery. This Research Topic comprises one brief research report and five original research articles ranging from association analysis to identification of protein-truncating and rare missense variants in diverse populations, and causal analysis of risk factors on various diseases such as cardiovascular disease and women's reproductive health. Keratoconus (KTCN) is a multifactorial disease with a complex etiology involving multiple genes, as well as behavioral, lifestyle, and environmental factors. Building on their previous work, Nowak-Malczewska et al. identified six significantly upregulated and four downregulated KTCN pre-miRNAs in the RNA-seq data of the studied corneal samples derived from patients with KTCN and controls. The highest difference in expression between KTCN and non-KTCN corneas was reached by the upregulated miR-184. The identified differentially expressed miRNAs might contribute to KTCN pathogenesis via disruption of the extracellular matrix organization and signal transduction pathways that they have already indicated as causative in their study.Gene panel testing of large population-based case-control studies has recently provided improved estimates of the prevalence of pathogenic variants (PVs) and the respective magnitude of breast cancer risk associated with these PVs. Zanti et al. used panel sequencing data generated as part of the Breast Cancer Association Consortium (BCAC) BRIDGES project to investigate the prevalence of PVs and rare missense variants in more than 2,000 samples from the MASTOS study, a population-based case-control study of breast cancer in Cyprus. The authors found that protein-truncating variants (PTVs) in BRCA2 and ATM were associated with a high risk of breast cancer, whereas PTVs in BRCA1 and PALB2 were associated with a high risk of estrogen receptor negative disease. Among participants with a family history of breast cancer, PTVs in ATM, BRCA2, BRCA1, PALB2 and RAD50 were associated with an increased risk of breast cancer. The authors also confirmed the effect of family history, age at diagnosis and tumor subtype as critical factors for risk stratification of women with breast cancer in the general population of Cyprus.Mendelian randomization (MR) is a powerful epidemiological method that uses genetic variants as instrumental variables to assess the causal relationships between risk factors and health outcomes. It leverages the principle that genetic variants are randomly assorted at conception, mimicking the effects of a randomized controlled trial. MR studies are particularly valuable in genetic epidemiology for identifying causal relationships in situations where traditional observational studies may be prone to bias. This approach has been applied to a variety of health conditions, including the four MR studies featured within this research topic, each contributing insights into their respective areas.Rukh et al. investigated the association between a derived measure for well-being with cardiovascular disease risk (i.e., atrial fibrillation, heart failure, myocardial infarction, and ischemic stroke) using two-sample MR. The genetically predicted well-being measure was causally associated with reduction in both heart failure and myocardial infarction. The well-being association was found to be mainly driven by depressive symptoms. Their results suggest that improving psychological wellbeing may help in reducing the burden of cardiovascular disease.As several epidemiologic studies have suggested that smoking initiation, alcohol and coffee consumption are associated with adverse female reproductive health, Jiang et al. in a twosample MR investigated reproductive hormones and menstruation phenotypes. They found that smoking had a significant causal association with lower sex hormone-binding globulin levels and earlier age at menopause. They further observed suggestive evidence that alcohol consumption was associated with lower total testosterone levels and earlier age at menopause. Coffee consumption did not show an association with any of the female reproductive variables examined. As males were included in the analyses, further research is needed to understand the role of smoking initiation, alcohol and coffee consumption in female populations.Liu et al. used two-stage MR to investigate a previously observed association between endometriosis and gut microbiota. Anaerotruncus, Desulfovibrio, Haemophilus, and Holdemania showed causal association with endometriosis. Holdemania and Ruminococcaceae UCG002 exert reversible, stage-specific impacts. For mild endometriosis, the study team identified increased causal associations with Eubacterium brach group, Family_XIII AD3011 group, and Ruminococcaceae UCG002. For moderate to severe endometriosis, Bacteroides, Holdemania, and Lachnospiraceae NK4A136 groups were identified as protective factors. As specific gut microbiota exhibit causal effects on endometriosis and specific endometriosis stages, opportunities exist for developing new treatments for endometriosis.As the causes of primary dysmenorrhea are not fully understood and with a goal to gain novel insights into the clinical management of dysmenorrhea, Li et al. investigated the causal link between phosphatidylcholine (PC), a phospholipid involved in biological membranes, and dysmenorrhea using two-sample MR. They found a significant positive association between increased PC levels and dysmenorrhea and suggested that together with its metabolite lysoPC, these molecules may play a regulative role in uterine smooth muscle contractions through a signaling pathway linked to lipid metabolism.Each of these papers represents a unique contribution to the field, and together they illustrate the impact of women in genetic epidemiology. In addition to showcasing science, this Research Topic celebrates the achievements of women in a field that, like many others, has historically faced gender disparities. By providing a platform for women scientists to share their work, we aim to foster a more inclusive scientific community that values the contributions of all researchers, regardless of gender.