Gestational diabetes mellitus, a heritable metabolic disorder and the most common pregnancy-related condition, remains understudied regarding its genetic architecture and its potential for early prediction using genetic data. Here we conducted genome-wide association studies on 116,144 Chinese pregnancies, leveraging their non-invasive prenatal test sequencing data and detailed prenatal records. We identified 13 novel loci for gestational diabetes mellitus and 111 for five glycemic traits, with minor allele frequencies of 0.01-0.5 and absolute effect sizes of 0.03-0.62. Approximately 50% of these loci were specific to gestational diabetes mellitus and gestational glycemic levels, distinct from type 2 diabetes and general glycemic levels in East Asians. A machine learning model integrating polygenic risk scores and prenatal records predicted gestational diabetes mellitus before 20 weeks of gestation, achieving an area under the receiver operating characteristic curve of 0.729 and an accuracy of 0.835. Shapley values highlighted polygenic risk scores as key contributors. This model offers a cost-effective strategy for early gestational diabetes mellitus prediction using clinical non-invasive prenatal test.

Platelet count reduction occurs throughout pregnancy, with 5% to 12% of pregnant women being diagnosed with gestational thrombocytopenia (GT), characterized by a more marked decrease in platelet count during pregnancy. However, the underlying biological mechanism behind these phenomena remains unclear. Here, we used sequencing data from noninvasive prenatal testing of 100 186 Chinese pregnant individuals and conducted, to our knowledge, the hitherto largest-scale genome-wide association studies on platelet counts during 5 periods of pregnancy (the first, second, and third trimesters, delivery, and the postpartum period) as well as 2 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. Interestingly, 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 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. Those with 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.

Maintaining normal thyroid function is crucial in pregnancy, yet thyroid dysfunction and the presence of thyroid peroxidase antibodies (TPOAb) affect 0.5% to 18% of pregnant women. Here, we conducted a genome-wide association study (GWAS) of eight thyroid traits, including two thyroid-related hormones, four thyroid dysfunctions, and two thyroid autoimmunity measurements among 85,421 Chinese pregnant women to investigate the genetic basis of thyroid function during pregnancy. Our study identified 176 genetic loci, including 125 previously unknown genome-wide associations. Joint epidemiological and Mendelian randomization analyses revealed significant associations between the gestational thyroid phenotypes and gestational complications, birth outcomes, and later-age health outcomes. Specifically, genetically elevated thyroid-stimulating hormone (TSH) levels during pregnancy correlated with lower glycemic levels, reduced blood pressure, and longer gestational duration. Additionally, TPOAb and thyroid functions during pregnancy share genetic correlations with later-age thyroid and cardiac disorders. These findings provide insights into the genetic determinants of thyroid traits during pregnancy, which may lead to new therapeutics, early pre-diagnosis and preventive strategies starting from early adulthood.

Intrahepatic cholestasis of pregnancy (ICP) is the most common and high-risk liver disorder during pregnancy, with varying prevalence across populations. Our understanding of the mechanisms underlying ICP and population-level differences remains limited. This study delves into the genetic etiology of ICP in East Asians, drawing comparisons with Europeans to comprehend ICP etiology in the context of genetic background and evolution. We conducted the hitherto largest-scale genome-wide association study on fasting total serum bile acids (TBA) and ICP in 98,269 Chinese pregnancies. The findings were replicated in three cohorts and compared with European populations. Additionally, phenome-wide association and spatio-temporal evolution analyses were employed to investigate the function and evolutionary patterns of ICP-associated loci. We identified eight loci for fasting TBA and four for ICP, including ten novel loci. Notably, we discovered an East Asian-specific locus within a 0.4 Mbp region at 14q24.1, which increases fasting TBA by 6.12 μmol/L and ICP risk by 16.56-fold per risk allele (95% CI 16.43 to 16.69, p = 7.06×10^-381). Phenome-wide association and spatial-temporal evolution analyses revealed that this 14q24.1 ICP risk locus confers resistance to hepatitis B and has become prevalent in East and Southeast Asia within the last 3,000 years. We uncovered a distinct genetic etiology of ICP in East Asians, likely linked to a historic HBV epidemic in East and Southeast Asia within the last 3,000 years. These findings enhance our understanding of ICP pathophysiology and offer potential for more precise detection, assessment, and treatment of the disorder. This study provides novel insights into the genetic basis of intrahepatic cholestasis of pregnancy (ICP) in East Asian populations, where little was previously known. The identification of the East-Asian-specific 14q24.1 locus, associated with both fasting total serum bile acids and ICP, and its connection to a historical hepatitis B epidemic emphasize the importance of incorporating population-specific history into disease research. These findings are crucial for researchers studying pregnancy-related liver disorders and clinicians providing care to pregnant women, enabling more accurate screening, risk assessment, and targeted interventions for ICP.

Objective: Genome-wide non-invasive prenatal testing (GW-NIPT) for prenatal screening has been widely implemented. However, the related clinical data is still insufficient. Here, we evaluated the clinical performance of GW-NIPT as a first-tier screening test for detecting fetal aneuploidy and copy number variation (CNV). Methods: The study included 59,877 pregnant women who underwent GW-NIPT at Shenzhen Baoan Women’s and Children’s Hospital, China, from November 2017 to May 2021. NIPT was performed on the BGISEQ-500 platform. Fetal karyotype analysis, chromosomal microarray analysis (CMA) and fluorescence in situ hybridization were used for invasive diagnostic procedures, and postnatal outcomes were collected. Results: Among 59,877 pregnant women who underwent GW-NIPT, 59,771 were successfully tested. Of these, 499 (0.83%) were identified with 504 high-risk fetal chromosomal abnormalities, including 5 cases each carrying two distinct abnormalities. Follow-up analysis demonstrated that GW-NIPT sensitivity exceeded 97% for fetal aneuploidies and was 63.6% for CNV (≥5 Mb). The positive predictive values for T21, T18, T13, sex chromosome aneuploidy, rare autosomal aneuploidy, and CNV (≥5 Mb) were calculated as 83.1%, 25.8%, 10.3%, 51.9%, 2.0%, and 33.9%, respectively. For confirmed fetal mosaicism, the detection rate of NIPT was 70.6%, which was consistent with that of CMA (70.6%). Conclusions: GW-NIPT has high sensitivity in screening fetal aneuploidy and moderate clinical utility in detecting CNV and fetal mosaicism, demonstrating that GW-NIPT holds significant application value in current and future prenatal screening procedures.