Proteome-Wide Mendelian Randomisation Study of Adverse Perinatal Outcomes

Despite significant advances in pre- and postnatal care over the last century, adverse pregnancy related events still occur frequently. We used Mendelian randomisation (MR) to investigate potential causal effects of the mother's and fetal blood proteome on pregnancy related outcomes including birthweight, placental weight, preeclampsia, and sporadic miscarriage. We generated a list of genetic instruments to act as proxies for plasma proteins by combining two recent large protein GWAS (4719 proteins N = 35,559 individuals; 4775 proteins N = 10,708 individuals). We identified 1724 proteins with valid cis-pQTLs for use as genetic instruments. We identified evidence for causal relationships (MR Bonferroni corrected p_Bonferroni < 2.90 × 10^-5) involving fetal effects and/or maternal effects on birthweight and preeclampsia. Increased levels of PSG7 and BCMA and decreased levels of VLCAD, INHBB, and PLCG1 in the fetal circulation were potentially causal for increased birthweight. Similarly, increased levels of LIMA1 and decreased levels of VLCAD, FBLN3, and galectin-4 in the maternal circulation were potentially causal for increased birthweight. Decreased levels of SERPINE2 and SIGLEC6 were potentially causal for increased risk of preeclampsia. We did not find any significant effects of proxied maternal or fetal proteins on placental weight or sporadic miscarriage, perhaps due to the smaller size of their GWAS meta-analyses. Our results implicate several proteins that may be involved in the aetiology of perinatal phenotypes that will need to be replicated in independent datasets.