In a first, study links maternal genes to risk of pregnancy loss

A new study is the first to identify genetic variants linked with chromosomal abnormalities that can lead to pregnancy loss.

About half of pregnancy losses in the first trimester are caused by aneuploidy, a condition in which cells have an abnormal number of chromosomes. Studies show that aneuploidy is much more common in egg cells than in sperm cells and that it affects an increasing proportion of a person's eggs with age.

Aneuploidy in eggs can contribute to infertility and pregnancy loss in women, as well as genetic disorders in children, some of which can cause severe disability or death. But currently, little is understood about the individual factors linked to a greater risk of producing aneuploid eggs and, in turn, aneuploid embryos.

"I think that's a big blind spot for our field," said Rajiv McCoy, an associate professor of biology at Johns Hopkins University. McCoy and colleagues aimed to address this blind spot in a new study, published in January in the journal Nature.

They used clinical genetic testing data from over 139,000 embryos created for in vitro fertilization (IVF) to examine the relationship between maternal genetic variants and the incidence of aneuploid embryos. The dataset included 22,850 mothers, whose ages ranged from about 20 to nearly 56 years old. The average age was about 36 years old, around the age women's risk of producing aneuploid embryos sharply increases.

"We previously didn't have any very well-characterized associations between genetic variation in the mother's genome and risk of producing eggs with aneuploidy," McCoy told Live Science.

The researchers performed genome-wide association studies, meaning they looked for statistical links between gene variants carried by the study participants and certain traits — in this case, the incidence of aneuploidy. They also analyzed the transcriptome, meaning the RNA inside cells; this genetic cousin of DNA carries instructions for making proteins and can give a snapshot of which genes are active.

The strongest association identified was with specific versions of SMC1B, a gene for a key protein that helps hold the two halves of chromosomes together. Another significant association was drawn to C14orf39, which helps mediate important interactions between chromosomes as cells divide.

The study provides insight into aneuploidy's relationship to a process called "crossover recombination," in which chromosomes exchange chunks of DNA during the formation of an egg or sperm cell. McCoy's team observed that crossover count — the number of DNA exchanges that happen during this process — was lower in aneuploid embryos. That supported previous findings that linked errors in crossover recombination, which can cause issues with chromosome separation during cell division, to a greater likelihood of aneuploidy.

But the study also uncovered something new about this relationship: The genetic variants tied to aneuploidy risk are also involved in crossover recombination. "The same machinery that's influencing recombination is the machinery that's influencing risk of producing these aneuploidies," McCoy said.

"This helps us understand how all of these traits are tied together," said Shai Carmi, a professor of computational and statistical genetics at the Hebrew University of Jerusalem who was not involved in the research. "What are the risk factors that make some women have more aneuploidy and, therefore, lower fertility?"

Even for those not experiencing infertility, pregnancy loss is incredibly common.

"About 10% to 20% of clinically recognized pregnancies end in miscarriage," McCoy said. "But we actually think that about half of all conceptions are lost before birth, many of them very early on in development."

In uncovering the shared genetic basis underlying both crossover recombination and aneuploidy, this study underscores the fact that crossovers play an essential role in ensuring that the correct number of chromosomes end up in a given egg, so that an eventual pregnancy is viable.

Because each genetic variant tied to aneuploidy can explain only a small part of an individual's overall risk, it's too early for these findings to be applied to actual patients. Still, "that doesn't mean that it's not possible, in the future, to get better predictions of people's risk," McCoy said. "And this provides one clue as to what we should be looking for."

These findings could also serve as a starting point for further research aimed at developing therapies and diagnostics to help reduce pregnancy loss. That said, McCoy also thinks simply knowing more about the mechanisms behind pregnancy loss is meaningful in itself.

"I personally think that the value of this study is more fundamental," he said. "It's helping us understand who we are as humans."