Integrating genomic studies of gestational duration and birth weight to understand maternal and fetal causes of adverse pregnancy outcomes and links with later diseases

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Project Summary/Abstract Gestational duration and birth weight are primary indicators of pregnancy outcomes. They are associated with perinatal morbidity and mortality and also with childhood and adult disorders. In the past several years, we have made substantial progress in the genomic research of gestational duration and birth weight. First, we conducted large-scale genome-wide association (GWA) studies and identified six maternal genomic loci associated with gestational duration, and 190 maternal or fetal loci associated with birth weight. Second, we developed statistical methods to dissect the maternal and fetal genetic effects on birth outcomes. Third, we have studied the causal relationships between maternal phenotypes and birth outcomes as well as the life course associations between birth outcomes and late onset disorders. Despite these successes, there is a major gap in previous genomic studies – they usually targeted either gestational duration or birth weight separately albeit these two birth outcomes are statistically correlated and biologically related. To bridge this gap, we – the leading investigators who previously focused on either gestational duration or birth weight separately – have committed to work together and integrate the genomic research of gestational duration or birth weight. We propose a novel statistical approach to jointly model the maternal and fetal genetic effects on gestational duration and fetal growth. Specifically, we will 1) use birth weight as a surrogate for gestational duration and leverage UK Biobank birth weight data for more powerful GWA discoveries of genomic loci associated with gestational duration; 2) disentangle and replicate maternal and fetal effects by integrated genomic analysis in mother/infant duos; and 3) integrate genomics and phenomics to resolve the complexity of birth outcomes and their links with late onset diseases. These cohesive study aims transcend conventional GWA studies and the results generated from this study will increase our knowledge of the biology of human birth timing and fetal growth. This study also has the potential to inform preventative and therapeutic measures for preterm birth and adverse pregnancy outcomes.