Multi-ancestry study reveals genetic risk factors for two common pregnancy complications

Pregnancy complications related to hypertension, or high blood pressure, affect 15 percent of childbearing women and are a leading cause of maternal death worldwide. Without prompt diagnosis and treatment, hypertensive disorders of pregnancy (HDPs) can lead to organ failure and potentially fatal complications. But scientists lack the tools to predict, prevent, and treat them. 

Researchers at the Broad Institute of MIT and Harvard are beginning to uncover genetic factors contributing to gestational hypertension and preeclampsia, two common HDPs. The findings, which appeared recently in Nature Medicine, provide insight into the biological mechanisms underlying pregnancy complications and could help improve patient care. 

By studying previously published genomes of individuals with HDPs, the researchers identified 18 places in the genome that influence an individual’s risk of developing one of these conditions. They also developed polygenic risk scores, which distill a person’s likelihood of developing a condition down to a single number based on their genes. The scores could help doctors identify and treat at-risk individuals earlier in pregnancy with existing but underutilized strategies such as low-dose aspirin.

“This is potentially an ideal use case for polygenic risk scores to refine risk assessment,” said Michael Honigberg, a co-first author on the study, associate member at the Broad, and a cardiologist at Massachusetts General Hospital. “Not only is this a population where clinical risk factors do a poor job predicting who will develop these conditions, but there’s also actually something we can do with better predictions.”

The work was co-led by senior author Pradeep Natarajan, an associate member at the Broad, the director of preventive cardiology at Massachusetts General Hospital, and an assistant professor of medicine at Harvard Medical School. Buu Truong, a computational researcher and postdoctoral fellow in Natarajan’s lab, was a co-first author as well.

Maternal meta-analysis

Scientists have long thought that HDPs are caused in part by genetics. About one-third of a person’s risk of developing preeclampsia is estimated to stem from genetic causes, but until now, researchers weren’t sure which parts of the genome influenced risk.

Honigberg, Natarajan, and their team analyzed separately the DNA of about 11,000 individuals with gestational hypertension (high blood pressure that arises during pregnancy) and 20,000 individuals with preeclampsia/eclampsia (gestational hypertension with additional symptoms such as high levels of protein in the urine and seizures, as in eclampsia). The cohort, which also included more than 400,000 controls for each condition, has the widest range of ancestries in a genome-wide association study of HDPs to date.

The team identified 18 locations in the genome, associated with preeclampsia/eclampsia and/or gestational hypertension, 12 of which had not been identified previously. This suggests that a range of biological pathways related to blood vessel growth, dysregulation of the immune system, embryo development, kidney function, and hormone signaling play a role in the conditions and could be targeted by future therapies. Honigberg was particularly surprised to find that patients with lower levels of signaling by peptides produced in the heart were predisposed to developing HDPs, suggesting that doctors could use synthetic peptides — similar to some developed previously — to prevent or treat them.

“The possibility that a cardiac-derived molecule influences placental development has been suggested in mice before, but this is the first human genetic confirmation of that finding,” Honigberg said. “It’s a newly appreciated phenomenon that opens a lot of future avenues of research.”

The researchers also used the data to develop polygenic risk scores, which accurately predicted both preeclampsia and gestational hypertension in new patient cohorts even without conventional clinical risk factors. When used together, polygenic risk scores and risk factors identified nearly half of all patients with preeclampsia/eclampsia, up from just 18 percent pinpointed by risk factors alone.

The authors say the scores could be used in a clinical setting to identify and treat at-risk patients earlier with low-dose aspirin, currently given to individuals with certain risk factors. Patients with polygenic risk of HDPs could also make lifestyle changes to minimize other sources of risk, such as obesity.

In the future, the researchers plan to continue studying the function of the genetic loci identified by their analysis. Honigberg also wants to use the data to shed light on why some patients develop hypertension in multiple pregnancies and others do only once.