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Study Spells Out Separate Parental, Fetal Genome Contributions to Fetal Growth

NEW YORK – Some genetic variants in the fetal genome have effects on fetal growth that are at odds with those found in parental genomes, according to new research from investigators at Amgen subsidiary Decode Genetics, the University of Iceland, and elsewhere.

"For the fetus to survive outside its mother's womb, it has to have … maturity, and birth weight is one measure of all of that," said Kari Stefansson, senior and co-corresponding author of the study. "So it's an important part of human diversity, and to tease apart what is conferred by variants in the sequence of the fetus versus the sequence of the mother that is not transmitted to the fetus is an important one: It relates to this ever-present question about the contributions of genetics versus environment." Stefansson is the founder and CEO of Decode and an investigator at the University of Iceland's faculty of medicine.

For their research, published in Nature Genetics on Monday, Stefansson and his colleagues conducted a series of birth weight genome-wide association studies informed by haplotype-phased genomes from parent-child trios in Iceland to focus in on hundreds of fetal growth-associated variants. That set included nearly two dozen variants with apparent parent-of-origin effects, along with variants that appeared to have distinct effects when found in either the fetal genome or in the genome of mothers carrying those fetuses.

"When you're looking at this interplay between the parental genome — the maternal genome — and the fetal genome, the mother is basically the environment of the individual for the first nine months," Stefansson said. "All life on Earth is a consequence of DNA molecules that are in a dynamic equilibrium with the environment. In this case, during these nine months, the [fetal] environment is the mother and nothing else."

The team focused in on 243 variants that were independently linked to fetal growth through a GWAS meta-analysis that included nearly 423,700 babies with available genetic data and birth weight from the Icelandic birth register, the Early Growth Genetics consortium, or the UK Biobank, as well as more than 270,000 of their mothers. Those data were complemented by GWAS analyses focused on birth length, neonatal leanness, and paternal contributors to such fetal growth features.

With the help of phased haplotype profiles for the fetal, maternal, and paternal genomes from Iceland, meanwhile, the investigators identified the modes of transmission for 141 of the fetal growth-related SNPs and highlighted 22 fetal growth-associated variants showing different effects depending on whether they were inherited maternally or paternally.

"We are in a privileged position in Iceland in that we can haplotype, we can long-range phase, the genome of everyone," Stefansson said. "So we can easily separate what comes from the mother, what comes from the father. And we can easily separate the parts of the maternal and the paternal genome that are not transferred to the child versus the things that are transferred to the child."

From the subset of growth-associated SNPs with known transmission patterns, the team went on to define four variant categories based on their apparent growth effects when appearing in the fetal genome or the maternal genome.

While some variants appeared to have an effect in the fetal genome only, or only in parental genomes, other variants had opposite effects on fetal weight, depending on whether they were found in the fetal or maternal genome — patterns the researchers explored in more detail by developing haplotype-specific polygenic risk scores. In particular, they noted that variants previously implicated in diabetes risk appeared to have opposing birth weight effects when found in the fetal genome or the maternal genome.

If those diabetes-associated variants are present in the maternal genome, but not passed on to the fetus, they tend to increase birth weight, Stefansson explained. But diabetes-related variants that do get transmitted to the fetal genome appeared to correspond with lower birth weight.

For the most part, though, the researchers found that the fetal genome played an outsized role in an infant's birth weight, apparently accounting for much of the relationship that has been described between blood pressure-related variants and lower-than-usual birth rate. Still, some parental variants did show pronounced effects on birth weight, including SNPs in maternal pathways related to glycemic traits, which may affect the fetal environment found within a mother during development.

"With the exception of positive maternal contribution to birth weight through variants that associate with glycemic traits, probably through increased maternal glucose, most of the effect on birth weight is through the fetal genome," the authors reported, noting that "variants that associate with blood pressure exert most of their negative effect on birth weight through the fetal genome."