Major genetic breakthrough reveals hidden causes of severe morning sickness in pregnancy

The same research team previously identified the hormone-producing gene GDF15 as a major contributor to pregnancy-related nausea and vomiting. The latest findings greatly expand scientists' understanding of the genetics behind HG and may point toward new ways to prevent or treat it.

A Severe and Often Misunderstood Condition

HG affects about 2% of women and causes extreme nausea and vomiting that can make eating and drinking very difficult. In serious cases, the condition can lead to severe malnutrition and threaten the health of both the mother and baby.

For years, HG was poorly understood and sometimes dismissed as a psychological problem. A growing body of evidence now shows that it has strong biological and genetic roots.

For the largest genetic investigation of HG conducted so far, scientists from the Keck School of Medicine of USC and collaborating institutions analyzed information from 10,974 women with the condition and 461,461 controls. The participants represented European, Asian, African and Latino ancestries.

Published in Nature Genetics, the results provide important new insight into why HG develops and offer hope for improved care.

"Because this is the largest study of HG ever conducted, we've been able to tease out important new details that were previously unknown," said Marlena Fejzo, PhD, a clinical assistant professor of population and public health sciences in the Center for Genetic Epidemiology at the Keck School of Medicine, who led the present study and earlier research linking GDF15 to HG. "The fact that we've studied women from multiple ancestry groups suggests that these results may be generalizable across a broad population."

GDF15 Remains the Strongest Genetic Link

The researchers identified 10 genes associated with HG. Four had been linked to the condition previously, while six were newly discovered.

The most powerful association was with growth differentiation factor 15 (GDF15). This gene produces a hormone with the same name that increases sharply during pregnancy.

Previous work by Fejzo and an international research team showed that the severity of pregnancy sickness appears to depend partly on how sensitive a woman is to this hormone. Women who have lower GDF15 exposure before pregnancy because of a genetic mutation tend to experience more severe symptoms. Women who encounter higher levels before pregnancy generally have less severe nausea and vomiting.

The other genes identified in the new study are connected to pregnancy hormones, appetite, nausea, insulin regulation, metabolism, brain adaptation, and several pregnancy outcomes.

"Now that we've more than doubled the genes associated with HG, we can dig deeper into the biology behind this condition, as well as new possible pathways for treating it," Fejzo said.

Mapping the Genetic Basis of HG

To find the new associations, the team carried out a genome-wide association study (GWAS). This method searches across the entire genome for genetic differences that appear more often in people with a condition than in those without it.

The four genes already associated with HG were GDF15; GFRAL, which produces the receptor for the GDF15 hormone; and IGFBP7 and PGR, both of which help regulate placental development.

The six newly identified genes were FSHB, TCF7L2, SLITRK1, SYN3, IGSF11 and CDH9. Together, they offer additional clues about the biology of HG and may reveal new targets for treatment.

TCF7L2 is particularly notable because it is one of the strongest known genetic risk factors for type 2 diabetes. It has also been linked to gestational diabetes.

The gene may affect glucagon-like peptide-1 (GLP-1), a hormone produced in the gut that helps regulate blood sugar while also influencing appetite and nausea.

"This is a brand-new target, and it's not yet clear what it's doing in pregnancy," Fejzo said.

Appetite, Nausea and Learned Food Aversions

Several of the other newly identified genes are involved in appetite, nausea and brain plasticity, which refers to the brain's ability to learn and adapt to new information.

Fejzo suggests that the brain may begin linking certain foods with feelings of sickness. That process could produce intense and persistent food aversions during pregnancy, although additional research will be needed to determine whether this explanation is correct.

The scientists also found that some HG-related genes were connected to other pregnancy outcomes. These included shorter pregnancy length and preeclampsia, a serious condition involving high blood pressure.

New Possibilities for HG Treatment

Medications are available for HG, but current options do not work well for every patient. Even Zofran, considered one of the most effective treatments, provides only partial symptom relief for about half of those who take it.

The new genetic findings could reveal additional drug targets and may eventually help doctors select treatments according to a patient's genetic profile.

Fejzo and her colleagues have also received approval to begin a clinical trial involving metformin. The widely prescribed diabetes medication is known to raise GDF15 levels.

The researchers will investigate whether taking metformin before pregnancy can reduce sensitivity to GDF15. If successful, the approach could lessen nausea and vomiting or help prevent HG in women who have experienced the condition during an earlier pregnancy.

About This Research

In addition to Fejzo, the study's other authors are Xinran Wang, Qing Tan, Artem Kim, Steven Gazal, Chang Shu and Nicholas Mancuso from the Department of Population and Public Health Sciences and the Center for Genetic Epidemiology, Keck School of Medicine of USC, University of Southern California; Julia Zöllner, Sarah Finer and David A. van Heel from Queen Mary University of London, London, United Kingdom; Natàlia Pujol-Gualdo and Triin Laisk from the University of Tartu, Tartu, Estonia; the Estonian Biobank Research Team; the Genes & Health Research Team; Ben Brumpton, Laxmi Bhatta and Kristian Hveem from the Norwegian University of Science and Technology, Trondheim, Norway; Elizabeth A. Jasper, Digna R. Velez Edwards, Jacklyn N. Hellwege and Todd Edwards from Vanderbilt University Medical Center, Nashville, Tennessee; Gail P. Jarvik from the University of Washington Medical Center, Seattle, Washington; Yuan Luo from Northwestern University, Chicago, Illinois; Atlas Khan from Columbia University, New York, New York; Kimber MacGibbon from the Hyperemesis Education and Research Foundation, Clackamas, Oregon; Yuan Gao and Gaoxiang Ge from the Chinese Academy of Science, Shanghai, China; Inna Averbukh, Erin Soon and Michael Angelo from Stanford University, Stanford, California; Per Magnus from the Norwegian Institute of Public Health, Oslo, Norway; Stefan Johansson, Pål R. Njølstad and Marc Vaudel from the University of Bergen, Bergen, Norway.

The research received support from federal and private organizations around the world, including the National Institutes of Health, under grants R01HG012133, R01CA258808, R01GM140287 and U54HG013243.