USC researchers have discovered nine additional genes associated with the most serious pregnancy disorder, hyperemesis gravidarum (HG). Six of these genes had not previously been associated with this condition.
The same research team previously identified the hormone-producing gene GDF15 as a major cause of pregnancy-related nausea and vomiting. The latest findings greatly expand scientists’ understanding of the genetics behind HG and may point to new ways to prevent or treat it.
Serious symptoms that are often misunderstood
HG affects about 2% of women and can cause extreme nausea and vomiting, making it very difficult to eat and drink. In severe cases, this condition can cause severe malnutrition, threatening the health of both mother and baby.
For many years, HG was poorly understood and sometimes dismissed as a psychological problem. There is now growing evidence that this has strong biological and genetic roots.
For the largest HG genetic study ever conducted, scientists at the Keck School of Medicine of Southern California and collaborating institutions analyzed information from 10,974 women with HG and 461,461 controls. Participants were of European, Asian, African, and Latinx descent.
Published in natural geneticsthis result provides important new insights into why HG was developed and offers hope for improved care.
“This is the largest study of HG ever conducted, so we were able to uncover important new details that were previously unknown,” said Marlena Fezzo, Ph.D., clinical assistant professor of population and public health sciences in the Center for Genetic Epidemiology at the Keck School of Medicine, who led this study and previous research linking GDF15 and HG. “The fact that we studied women from multiple ancestral groups suggests that these results may be generalizable across broad populations.”
GDF15 remains the strongest genetic link
Researchers identified 10 genes associated with HG. Four cases were previously associated with the condition, and six were newly discovered.
The strongest association was growth differentiation factor 15 (GDF15). This gene produces a hormone of the same name that increases rapidly during pregnancy.
Previous research by Fejzo and an international team of researchers showed that the severity of the disease during pregnancy appears to depend in part on how sensitive the woman is to this hormone. Women who have less exposure to GDF15 before pregnancy due to genetic mutations tend to experience more severe symptoms. Women who reach high levels before pregnancy generally experience less severe nausea and vomiting.
Other genes identified in the new study are associated with pregnancy hormones, appetite, nausea, insulin regulation, metabolism, brain adaptation, and several pregnancy outcomes.
“Now that the genes associated with HG have more than doubled, we can dig deeper into the biology behind this condition and find new potential pathways for treatment,” Fejzo said.
Mapping the genetic basis of HG
To find new associations, the research team conducted genome-wide association studies (GWAS). This method searches the entire genome for genetic differences that occur more frequently in people with the disease than in those without.
The four genes already associated with HG were GDF15; GFRAL produces receptors for the GDF15 hormone. And IGFBP7 and PGR both help regulate placental development.
The six newly identified genes were FSHB, TCF7L2, SLITRK1, SYN3, IGSF11, and CDH9. Taken together, these may provide further clues about the biology of HG and reveal new therapeutic targets.
TCF7L2 is of particular interest because it is one of the strongest known genetic risk factors for type 2 diabetes. It has also been linked to gestational diabetes.
This gene may influence glucagon-like peptide-1 (GLP-1), a hormone produced in the intestine that helps regulate blood sugar and also affects appetite and nausea.
“This is a completely new target, and it’s not yet clear what effects it has during pregnancy,” Fezzo said.
Appetite, nausea, and learned food aversions
Some 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 to associate certain foods with feeling sick. This process may result in intense and persistent food aversions during pregnancy, but additional research is needed to determine whether this explanation is correct.
Scientists also found that some HG-related genes are associated with other pregnancy outcomes. These include preeclampsia, a serious condition associated with shortened gestational age and high blood pressure.
New possibilities for HG treatment
Although medications are available for HG, current options do not work well for all patients. Even Zofran, considered one of the most effective treatments, provides only partial relief for about half of those who take it.
New gene discoveries may reveal additional drug targets and ultimately help doctors choose treatments depending on a patient’s genetic profile.
Fejzo and his colleagues also received approval to begin clinical trials on metformin. Commonly prescribed diabetes medications are known to increase GDF15 levels.
The researchers plan to investigate whether taking metformin before pregnancy reduces sensitivity to GDF15. If successful, this approach could reduce nausea and vomiting and help prevent HG in women who experience this condition during early pregnancy.
About this study
In addition to Fejzo, other authors of the study are Xinran Wang, Qing Tan, Artem Kim, Steven Gazal, Chang Shu, and Nicholas Mancuso of the Keck School of Population and Public Health Department and Genetic Epidemiology Center at the University of Southern California. Julia Zöllner, Sarah Finer and David A. van Heel from Queen Mary University of London, London, UK; Natalia Pujol-Guardo and Torin Rajsk of the University of Tartu, Tartu, Estonia; Estonian biobank research team. Gene and 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, Jacquelyn N. Helwege, and Todd Edwards of Vanderbilt University Medical Center in Nashville, Tennessee; Gail P. Jarvik of the University of Washington Medical Center, Seattle, Washington; Yuan Luo of Northwestern University in Chicago, Illinois; Atlas Kahn from Columbia University in New York, New York. Kimber McGibbon of the Hyperemesis Education and Research Foundation in Clackamas, Oregon; Yuan Gao and Gaoxiang Ge, Chinese Academy of Sciences, Shanghai, China; Inna Averbukh, Erin Soon, and Michael Angelo of Stanford University in Stanford, California; Per Magnus, Norwegian Institute of Public Health, Oslo, Norway; Stefan Johansson, Paul R. Njorstad, and Mark Voder of the University of Bergen, Bergen, Norway;
This research received support from federal and private organizations worldwide, including the National Institutes of Health under grants R01HG012133, R01CA258808, R01GM140287 and U54HG013243.
