The heritability of gestational age in a two-million member cohort: implications for spontaneous preterm birth

Abstract

Preterm birth (PTB), defined as birth prior to a gestational age (GA) of 37 completed weeks, affects more than 10% of births worldwide. PTB is the leading cause of neonatal mortality and is associated with a broad spectrum of lifelong morbidity in survivors. The etiology of spontaneous PTB (SPTB) is complex and has an important genetic component. Previous studies have compared monozygotic and dizygotic twin mothers and their families to estimate the heritability of SPTB, but these approaches cannot separate the relative contributions of the maternal and the fetal genomes to GA or SPTB. Using the Utah Population Database, we assessed the heritability of GA in more than 2 million post-1945 Utah births, the largest familial GA dataset ever assembled. We estimated a narrow-sense heritability of 13.3% for GA and a broad-sense heritability of 24.5%. A maternal effect (which includes the effect of the maternal genome) accounts for 15.2% of the variance of GA, and the remaining 60.3% is contributed by individual environmental effects. Given the relatively low heritability of GA and SPTB in the general population, multiplex SPTB pedigrees are likely to provide more power for gene detection than will samples of unrelated individuals. Furthermore, nongenetic factors provide important targets for therapeutic intervention.

Figure 1. Quantile-Quantile (QQ) plots for gestational age (GA) across two generations

(a) Paternal GA versus offspring GA. (b) Maternal GA versus offspring GA. In both panels, GA in the parent is represented on the x- axis and GA of the offspring on the y-axis. Each dot represents the value of (x,y) for different cumulative percentiles. The diagonal line represents the expected y = x relationship. Both the paternal and maternal plots show skewing below the diagonal, resulting in a bias towards individuals with larger GA as parents.