GENETIC FACTORS IN TIMING OF BIRTH

In Europe 5-12% of children are born preterm. It is the leading cause of neonatal death and long-term problems, such as cerebral palsy and autism. However, the biology behind human parturition and pregnancy is still poorly understood, and we have very little knowledge about what determines the exact time of birth. The Norwegian Mother Father and Child Cohort project provides a unique opportunity to study pregnancy and preterm birth in particular. The newest dataset contains genetic data on 70,000 families. These families also provided data about their everyday environment. We have a unique opportunity to explore this data and try to determine which factors increase the risk of preterm birth. It is likely that this outcome is caused by a combination of genes and environment. Since the current data contains fathers, mothers and children from the same families, we can also check whether the same genes have a different effect when inherited from the mother or father. All this is performed using modern statistical methods; using advanced computer simulations, it is even possible to test if a given factor is the true cause of preterm birth or just coincides. This project will be a collaborative effort between Norwegian institute of Public Health and some of the most prominent geneticists, statisticians and researchers of preterm birth in the world. Indeed, stemming from this project and a collaboration with Cincinnati Children's Hospital, genetic links for premature birth have been identified for the first time in over 40.000 women. We believe that increasing the number of participants will lead us to new insights and a better understanding of human pregnancy timing. This is why we are currently studying more than 100.000 women, which will be the largest ever known gestational age and preterm birth genome-wide association study. It is widely acknowledged that birth outcomes, such as birth and placental weight and gestational duration, are all interconnected. In order to better understand the interplay between these phenotypes, we are part in a major effort to discover genetic links with gestational duration, and birth and placental weight. In addition to this, we have just begun to dissect the origin of the effect of several characteristics on these birth outcomes, which is otherwise not possible using classical epidemiological data. As part of this project, and using Norwegian genomic data, we inferred causality effects for several phenotypes on gestational duration and birth weight. For example, while maternal height causally increases gestational duration, fetal length reduces it. Similarly, we have demonstrated that not only birth weight increases with gestational duration, but also birth weight has a negative effect on the duration of gestation. Disentangling the causal mechanisms and genetic correlations underlying these associations will clarify the aetiology of these birth outcomes and how they impact long-term health. Our results suggest that gestational duration is primarily determined by the maternal genome whereas fetal size measurements at birth are primarily determined by fetal genome. In this sense, mothers will have an influence of their offspring's birth weight by slightly modulating the duration of gestation. We also determined that inbreeding is not a major factor in preterm delivery etiology, but additional genetic factors affecting it remain to be discovered. We are leading an international effort to characterize the genetic basis of gestational duration, in the largest meta-analysis on gestational duration (>200,000 maternal samples); this allows us to understand parturition timing at the molecular level. The results show that gestational duration has been largely shaped by evolutionary forces, and a tightly controlled by sex hormones. We find evidence connecting, at the genome level, pre-eclampsia and the duration of gestation. The prediction of the expected date using genetic data is yet at its early days.

This project has allowed to build an international leading role in genetics of pregnancy, and more specifically, of gestational duration. This has been possible by means of increased collaboration with other international groups (the current work we are conducting is performed with the collaboration of over 20 groups from >10 different countries. While our research is primarily focused on genetic epidemiology, we have connected with basic researchers, which has resulted in a publication in Science Advances. Long term impacts for society include the characterization of gestational duration at the molecular level, which may ultimately lead to the development of rational strategies for treating impending labor or prolonged labor.

The human pregnancy and especially the timing of parturition are poorly understood in biological terms. Timing of birth is clearly determined by a significant contribution from genetic factors, but also by environmental factors. Both preterm and post-term deliveries are related to many adverse health outcomes. Preterm delivery is the leading cause of neonatal death. In Europe the reported rates are 5-12%. The long-term adverse health outcomes of preterm birth, like cerebral palsy and autism, render individuals to be dependent on health care systems. Using the new large genotyping HARVEST MoBa dataset with 11,000 family trios (mother, father, child), together with a rich collection of pregnancy-related medical variables and a world-unique set of validated environmental exposures (food items, vitamins, xenobiotics), we are in a privileged position to put under scrutiny molecular mechanisms regulating the timing of birth. Genomic methods with hypothesis-free and hypothesis-driven approaches will be used. We will scan for main genetic as well as gene-environment interaction effects, which is only possible in this type of data. We will take advantage of family-trio structure to identify maternal and paternal haplotypes, thus enabling investigation of imprinting effects. Preliminary findings in a smaller sample have shown significant results in both GxE and GWAS analyses. In a preliminary study on the smaller genotyped sample we for the first time used Mendelian Randomisation method to imply a direct causal relationship between maternal height and gestational age. The purpose with this project is to maintain the team and collaborations that we have developed at the Norwegian Institute of Public Health, but also further develop this knowledge infrastructure by collaboration with our long term prominent researchers, well known for their contributions to the fields of genetics and genomics, cohort-based research, preterm birth studies, and computational biostatistics.