Genetic studies of gestational duration and preterm birth

Abstract

The fine control of birth timing is important to human survival and evolution. A key challenge in studying the mechanisms underlying the regulation of human birth timing is that human parturition is a unique to human event - animal models provide only limited information. The duration of gestation or the risk of preterm birth is a complex human trait under genetic control from both maternal and fetal genomes. Genomic discoveries through genome-wide association (GWA) studies would implicate relevant genes and pathways. Similar to other complex human traits, gestational duration is likely to be influenced by numerous genetic variants of small effect size. The detection of these small-effect genetic variants requires very large sample sizes. In addition, several practical and analytical challenges, in particular the involvement of both maternal and fetal genomes, further complicate the genetic studies of gestational duration and other pregnancy phenotypes. Despite these challenges, large-scale GWA studies have already identified several genomic loci associated with gestational duration or the risk of preterm birth. These genomic discoveries have revealed novel insights about the biology of human birth timing. Expanding genomic discoveries in larger datasets by more refined analytical approaches, together with the functional analysis of the identified genomic loci, will collectively elucidate the biological processes underlying the control of human birth timing.

Advancing human health in the decade ahead: pregnancy as a key window for discovery

“…The field of developmental genomics applies state-of-the-art methodologies that strive to assist in bridging genotypes, physiology, and disease specifically to developmental processes from embryogenesis to parturition biology. From identification of genetic variants through sequencing or genome-wide association studies (GWAS) to defining nucleotide changes and investigating their downstream proteomic, metabolomic, and physiological consequences that may play an etiologic role in phenotypic consequences during pregnancy, numerous interrelated steps are logically aligned to chart the molecular maps underlying diseases 3 (Figure 1). Pregnancy phenotypes are shaped by the maternal, fetal, and placental genomes and epigenomes, and therefore, the genomic studies of these phenotypes would benefit from an integrative approach in mother-infant pairs.…”

“…As associations now exist for preterm birth and birthweight, these should drive functional studies to translate the findings to improvements in clinical care. 3,7 These functional studies should first indicate conclusive evidence for the actual genes responsible for the association because the nearest gene is not always the one relevant for the phenotype being investigated. 8 Subsequent investigations to determine the mechanism of action of the causal polymorphism can be performed in vitro, in cell lines, and now in vivo using gene-editing technologies.…”

Estimating indirect parental genetic effects on offspring phenotypes using virtual parental genotypes derived from sibling and half sibling pairs

“…There is increasing interest in estimating the indirect effect of parental genotypes on the phenotypes of their offspring (Bates et al 2018;Evans et al 2019;Kong et al 2018;Lawlor et al 2017). We and others have shown in human populations that the maternal and paternal genomes can indirectly affect a range of offspring traits including perinatal (Beaumont et al 2018;Evans et al 2019;Tyrrell et al 2016;Warrington et al 2019;Warrington et al 2018;Yang et al 2019;Zhang et al 2017;Zhang et al 2018) and later life phenotypes (Kong et al 2018;Warrington et al 2019). However, these sorts of analyses typically require large numbers of genotyped parent-offspring duos and trios in order to partition genetic effects into parental and offspring mediated components Moen et al 2019).…”

Haplotype-based analysis distinguishes maternal-fetal genetic contribution to pregnancy-related outcomes

“…The above approaches have helped explain a large proportion of the missing heritability in various complex diseases and quantitative traits. Nevertheless, they are less suited for pregnancy phenotypes which are simultaneously influenced by direct fetal genetic effects and indirect parental effects [21][22][23][24] . To date, only a few studies have attempted to distinguish maternal genetic effect 25,26 from fetal genetic effect in mother-child duos 21,23,27,28 .…”

“…We consider mother-child pairs as single analytical units consisting of three haplotypes corresponding to maternal transmitted (m1), maternal nontransmitted (m2) and paternal transmitted (p1) alleles 29,30 . Use of such an analytical unit provides an advantage over conventional approaches based on individual's genotype information by avoiding the confounding of m1 which can influence pregnancy phenotypes through both the mother and fetus (Fig 1a) 24 . We generate three separate genetic relatedness matrices M1, M2 and P1 using only m1, only m2 and only p1 respectively.…”