New Genetic Links Discovered for Severe Pregnancy Sickness

Researchers at the Keck School of Medicine of USC, working with international partners, have identified new genetic links to hyperemesis gravidarum (HG), the most severe form of pregnancy sickness. The findings, published in Nature Genetics, expand the biological understanding of a condition characterized by severe nausea and vomiting that can lead to significant maternal malnutrition and life-threatening complications for both the mother and fetus.

The study represents the largest genome-wide association study (GWAS) conducted on HG to date. Scientists analyzed genetic data from 10,974 affected women and 461,461 controls. To ensure a broad genetic perspective, the research included participants from multiple ethnicities, including African, Asian, European, and Latino populations.

Genetic Markers and New Discoveries

The research team identified a total of ten genetic associations. Four of these had been previously identified: GDF15, PGR, GFRAL, and IGFBP7. However, the study pinpointed six additional loci that had not been previously associated with the condition.

• SLITRK1
• SYN3
• IGSF11
• FSHB
• TCF7L2
• CDH9

The USC team had previously identified the GDF15 gene, which encodes a pregnancy-associated hormone, as a pivotal driver of nausea during gestation. This new data suggests that while GDF15 is a key factor, This proves only part of a more complex genetic landscape.

Biological Mechanisms and Expression

Downstream analyses provided insight into where these genes are expressed and how they affect the body. The researchers found that GDF15 and TCF7L2 are primarily expressed in extravillous trophoblasts. Interestingly, GDF15 showed opposing effects depending on whether the genotype was maternal or fetal.

In contrast, the PGR and IGFBP7 genes were found to be expressed primarily in maternal spiral arteries, with their effects limited to the maternal genome.

Further functional studies identified additional associations, including the protein ACP1 and antisense IGFBP7-AS1. These findings suggest that the etiological mechanisms of severe pregnancy sickness may involve pathways related to brain plasticity, insulin signaling, and appetite.

Broader Health Implications

The study also examined how these genetic loci correlate with other pregnancy outcomes. The researchers found that selected loci were associated with the duration of pregnancy, birth weight, abnormal pregnancy weight gain, and pre-eclampsia.

Historically, the biological underpinnings of hyperemesis gravidarum have been poorly understood. This research shifts the perspective toward a stronger biochemical and hereditary basis for the disorder, moving away from a nebulous understanding of the condition’s pathophysiology.

By using the GWAS methodology, the team was able to conduct an unbiased survey of the genome. This allowed them to detect associations between specific genetic variants and the presence of the disease without relying on preconceived targets.

These genetic insights provide new avenues for mechanistic exploration and the potential development of therapeutic avenues to treat the debilitating effects of HG.