Causal associations between genetically predicted placental weight and migraine.

BACKGROUND: Placental weight (PW) is a crucial factor in fetal development, influencing various health outcomes throughout life. This study investigates whether there is a causal relationship between PW and the risk of developing migraine. METHODS: Genetic variants associated with PW were obtained from the Early Growth Genetics Consortium, including fetal, maternal, and paternal genomes. Migraine data were derived from a 2022 genome‐wide association study meta‐analysis by the International Headache Genetics Consortium. Significant single nucleotide polymorphisms (SNPs) associated with PW were selected and analyzed to assess causality. RESULTS: Out of 11 PW phenotypes, six PW phenotypes with at least two SNPs each were included for Mendelian randomization analysis. The analysis revealed that PW (fetal effect, conditional on maternal and paternal genotype) was significantly associated with a reduced risk of migraine (odds ratio 0.81, 95% confidence interval 0.71–0.93; p = 0.003, false discovery rate adjusted p = 0.018). Sensitivity analyses confirmed the robustness of the findings, showing no evidence of heterogeneity or pleiotropy. CONCLUSION: Our findings suggest a potential causal relationship between fetal genetically predicted increased PW and a reduced risk of migraine in the offspring. Further research into the mechanisms underlying this association and its implications for migraine prevention is warranted. Plain Language Summary: The placenta is an important part of fetal development, and we wanted to see if there is a relationship between placental weight and the risk of developing migraine later in life. To explore this, we examined genetic data from more than 600,000 people and used a technique called Mendelian randomization, which treats naturally inherited genetic differences related to placental weight as a kind of "natural experiment" to test whether they directly affect migraine risk. The results showed a significant association between increased genetically determined fetal placental weight and a reduced risk of migraine; these findings provide insights into the potential influence of prenatal factors on migraine risk.