Genetic basis of pregnancy-associated decreased platelet counts and gestational thrombocytopenia

Abstract

Platelet counts reduction occurs throughout pregnancy, with 5-12% of pregnancies being diagnosed with gestational thrombocytopenia (GT), characterized by a decrease in platelet count during pregnancy. However, the underlying biological mechanism behind this altered platelet count phenomenon and GT remains unclear. Here, we utilized sequencing data from non-invasive prenatal test (NIPT) among 100,186 Chinese pregnancies and conducted the hitherto largest-scale genome-wide association studies (GWAS) on platelet counts at five periods of pregnancy (the first, second, and third trimesters, delivery, and the postpartum period), as well as two GT statuses (GT: platelet count < 150 × 109/L and severe GT: platelet count < 100 × 109/L). Our analysis revealed 138 genome-wide significant loci, explaining 10.4 to 12.1% of the observed variation. Attractively, we identified previously unknown changes in genetic effects on platelet counts during pregnancy for variants present in PEAR1 and CBL, with PEAR1 variants specifically associated with a faster decline in platelet counts. Furthermore, we found that variants present in PEAR1 and TUBB1 increased susceptibility to GT and severe GT. Our study provides the first insight into the genetic basis of platelet counts and GT in pregnancy, highlighting the critical role of PEAR1 in decreasing platelet counts during pregnancy and the occurrence of GT. Pregnancies carrying specific variants associated with declining platelet counts may experience a more pronounced decrease, thereby elevating the risk of GT. These findings lay the groundwork for further investigation into the biological mechanisms and causal implications of GT.

Utilizing Non-Invasive Prenatal Test Sequencing Data Resource for Human Genetic Investigation

“…In several companion papers stemming from this investigation, we delve into the genetic associations with approximately a hundred biomarker phenotypes used in pregnancy screening 21 . Of notable importance is our exploration of the genetic basis underlying common pregnancy disorders, such as gestational diabetes 18,22 and gestational thrombocytopenia 23 , particularly in the underrepresented Chinese population. Furthermore, we have garnered insights into the genetic architecture underpinning molecular phenotypes, including maternal 24 and newborn metabolites 25 .…”

“…We applied PLINK2 (v2.00a3.6LM) for PCA both before and after genotype imputation. Additionally, EMU (v.0.9) was used for PCA specifically before genotype imputation, aiming to assess the genetic structure of a dataset comprising 70,608 samples from one of the sequencing centers 23 . All PCA analyses were conducted on a set of non-duplicated 3,843,382 biallelic SNP variants with MAF ≥ 5%.…”