While estimates of total pregnancy losses vary considerably, about 15% of known pregnancies end in miscarriage, and many other conceptions do not survive past the very early stages of pregnancy. The primary cause for these losses is chromosomal abnormalities, like extra or absent chromosomes. Scientists have now analyzed data collected from over 140,000 IVF embryos to identify genetic differences that can increasethe risk of pregnancy loss. This work showed that there are certain genetic variants in some women that increase the risk of miscarriage. These findings, which were reported in Nature, may help scientists develop new methods to reduce the risk of pregnancy loss.
"This work provides the clearest evidence to date of the molecular pathways through which variable risk of chromosomal errors arises in humans," said senior study author Rajiv McCoy, a computational biologist at Johns Hopkins University. "These insights deepen our understanding of the earliest stages of human development and open the door for future advances in reproductive genetics and fertility care."
Chromosome errors typically arise in the egg and get more common as a mother's age increases. But genetic differences carried by potential moms could also increase the risk of chromosomal abnormalities in their offspring.
To find some of these genetic factors, researchers had to assess genetic data from 139,000 embryos and 23,000 sets of biological parents. Computational tools were used to find patterns in the data.
"You need large samples to be able to detect these small effects," McCoy said. "These insights deepen our understanding of the earliest stages of human development and open the door for future advances in reproductive genetics and fertility care."
The “huge sample sizes" gave their conclusions statistical “power” added McCoy. The team could then find associations between variants in maternal DNA and the risk of nonviable embryos.
The strongest associations were found between pregnancy loss and variations in genes related to chromosomal pairing, recombintion, and joining during egg formation. One gene known as SMC1B, for example, encodes for a portion of a chromosome-binding structure that is required for accurate chromosome segregation. These structures can also begin to degrade as women age.
"This finding is especially compelling," McCoy said, "because the genes that emerged from our study in humans are exactly the ones that experimental biologists have detailed over decades as critical for recombination and chromosome cohesion in model organisms like mice and worms."
Unfortunately, an individual’s risk of pregnancy loss is still challenging to predict with genetic data, because the known genetic variants that are relevant tend to only contribute a small amount of risk, added McCoy. But still, some of these genes are potential targets for drug development.
Sources: Johns Hopkins University, Nature
