Genomic approaches to understanding pregnancy phenotypes and birth outcomes and their links with long-term maternal and offspring health—the value of distinguishing maternal and fetal genetic effects

Abstract

Pregnancy is a biologically complex period with profound implications for maternal and offspring health. Adverse pregnancy outcomes such as pre-eclampsia, gestational diabetes, preterm birth, and growth restriction contribute substantially to maternal and neonatal morbidity and mortality, while also increasing risks of late-onset disorders in both mothers and children. Understanding the genetic basis of these pregnancy phenotypes and birth outcomes is therefore critical for advancing maternal–child health research. Unlike most human traits, pregnancy phenotypes are shaped by both maternal and fetal genomes, which are correlated but exert distinct influences. This dual genetic contribution presents unique challenges for genetic studies and necessitates specialized statistical approaches. In this review, we highlight recent methodological advances in genomic research designed to disentangle maternal and fetal genetic effects. We first discuss single-variant genome-wide association approaches, including conditional analyses, haplotype-based methods, structural equation modeling, and weighted linear models, which enable partitioning of maternal and fetal contributions. We then examine multi-variant strategies such as polygenic scores and Mendelian randomization, which provide insights into causal relationships, shared genetic architectures, and long-term health consequences. Finally, we explore approaches to characterizing the genetic architecture of pregnancy phenotypes, including methods for partitioning maternal and fetal genetic contributions and genetic correlation analyses with other health-related traits. Together, these genomic approaches have begun to clarify the complex interplay between maternal and fetal genomes in shaping pregnancy outcomes and their links to later-life health in both mothers and offspring. By emphasizing methodological innovation rather than empirical findings, this review provides a framework for future studies aiming to unravel the genetic underpinnings of pregnancy phenotypes and their connections with long-term health.