Autozygosity mapping and time-to-spontaneous delivery in Norwegian parent-offspring trios
Authors: Sole-Navais Pol , Bacelis Jonas , Helgeland Øyvind , Modzelewska Dominika , Vaudel Marc , Flatley Christopher , Andreassen Ole , Njølstad Pål R. , Muglia Louis J. , Johansson Stefan , Zhang Ge , Jacobsson Bo 
Published: June 2020

Parental genetic relatedness may lead to adverse health and fitness outcomes in the offspring. However, the degree to which it affects human delivery timing is unknown. We use genotype data from ≃25,000 parent-offspring trios from the Norwegian Mother, Father and Child Cohort Study to optimize runs of homozygosity (ROH) calling by maximising the correlation between parental genetic relatedness and offspring ROHs. We then estimate the effect of maternal, paternal, and fetal autozygosity and that of autozygosity mapping (common segments and gene burden test) on the timing of spontaneous onset of delivery. The correlation between offspring ROH using a variety of parameters and parental genetic relatedness ranged between −0.2 and 0.6, revealing the importance of the minimum number of genetic variants included in a ROH and the use of genetic distance. The optimized parameters led to a ≃45% increase in the correlation between parental genetic relatedness and offspring ROH compared to using predefined parameters. We found no evidence of an effect of maternal, paternal nor fetal overall autozygosity on spontaneous delivery timing. Yet, using autozygosity mapping for common and rare autozygous segments, we identified three maternal loci in TBC1D1, SIGLECs and EDN1 gene regions reducing median time-to-spontaneous onset of delivery by ≃2-5% (p-value< 2.3×10−6). We also found suggestive evidence of a fetal locus at 3q22.2, in the RYK gene region (p-value= 6.5×10−6). Autozygosity mapping may provide new insights on the genetic determinants and architecture of delivery timing beyond traditional genome-wide association studies, but particular and rigorous attention should be given to ROH calling parameter selection.

Author summary

Mating between relatives has an effect on offspring’s health and fitness in a number of species. In the offspring of genetically related parents, this is translated into long segments of the genome in the homozygous form (the same copy is inherited from each parent), but there is no consensus on how long these segments must be. In this study, we used dense genetic data from parent-offspring trios to optimize the detection of long segments of the genome. Our optimized long homozygous segments increased the correlation between parental genetic relatedness and offspring runs of homozygosity by ≃45% compared to widely used parameters. Furthermore, while preterm delivery is the global leading cause of mortality in children under 5 years, the degree to which long homozygous segments affect human delivery timing is unknown. We observed no maternal, paternal nor fetal effects of the proportion of the genome covered by homozygous segments on time-to-spontaneous delivery. However, by mapping these segments to the genome, we found evidence supporting three specific maternal segments falling on TBC1D1, SIGLECs and EDN2 gene regions to be associated with lower time-to-spontaneous onset of delivery. Future studies should assess the functional impact of these genes on spontaneous onset of delivery.