Marc Vaudel

When genetics meets endocrinology, wonderful discoveries happen. Here is a beautiful example. GDF15 (growth differentiation factor 15) is a circulating hormone secreted from multiple tissues including placenta and expectantly, its levels rises during pregnancy (first reported in 2000). The GDF15's receptor is expressed in the hindbrain and its activation causes nausea and vomiting (in addition to others). Pregnant women with hyperemesis gravidarum (HG) have higher GDF15 levels compared to pregnant women without this condition, which makes perfect sense, until you look at the genetic associations of HG, which tells us the opposite story. Common variants that increase GDF15 blood levels (in non-pregnant women) decrease the risk of HG (one'd expect to increase the risk). A missense variant in GDF15, which results in impaired secretion of GDF15 into the circulation, increases the risk of HG (one'd expect to decrease the risk). How's that possible? It turns out whether a women will experience increased nausea and vomiting with an acute rise in GDF15 levels during pregnancy depends on her pre-pregnancy GDF15 levels. Women genetically predisposed to have higher GDF15 get desensitized to the effects of GDF15 and as a result, they tolerate the pregnancy associated spike in GDF15 well. On the other hand, women genetically predisposed to have lower GDF15 levels (carriers of the missense variant) tolerate the pregnancy associated spike in GDF15 poorly resulting in HG. The impressive part of the study is the how the authors have elegantly uncovered this complex mechanism using an ingenious study design. I highly recommend reading this fantastic preprint, and clearly, this will be one of my favorite human genetics papers of 2023. Congrats to the entire team of authors 👏👏