NEW YORK – In a collection of new studies on pregnant women in China, research teams have demonstrated the feasibility of using noninvasive prenatal testing (NIPT) sequences to help untangle genetic contributors to pregnancy features and infant outcomes with phenome-wide association and genome-wide association study approaches.
In one of the studies, appearing in Cell Genomics on Wednesday, researchers at Xiamen University, BGI-Shenzhen, and Fu-Jen Catholic University used ultra-low coverage whole-genome sequencing to genotype more than 5.4 million SNPs in 25,639 Han Chinese women who underwent NIPT and gave birth at a hospital in Xiamen between 2015 and 2020.
Together with electronic health records from the Health Commission of Xiamen and NIPT-based variant data for 14,151 newborns, the maternal data made it possible to perform a phenome-wide association study spanning 268 maternal and 133 neonatal or early childhood phenotypes.
The team's analyses led to 2,883 variants at 442 loci that were linked to 26 maternal trait phenotypes such as gestational diabetes mellitus, psoriasis, asthma, or endometriosis, including sites implicated in many of the same traits in past genome-wide association studies.
The investigators also tracked down 21 maternal SNPs coinciding with nearly three-dozen neonatal phenotypes — a set that included variants associated with related phenotypes or conditions in both mothers and infants.
"Our findings provide a comprehensive view of the genetic background of non-gestational and gestational complications," co-senior and co-corresponding authors Qiyuan Li, a pediatrics, data science, and hematology researcher at Xiamen University, and Yulin Zhou, a researcher with Xiamen University's Women and Children's Hospital, and their colleagues wrote, adding that the analyses led to identifying "germline variants underlying the maternal-neonatal association of morbidities."
In another paper in Cell Genomics, investigators at Tongji Medical College, BGI Research, the University of Chinese Academy of Sciences, and other centers in China shared findings from their own genome-wide association and PheWAS analyses, which focused on 104 pregnancy-related phenotypes or birth outcomes in 20,900 Chinese women who had NIPT during pregnancy.
Using this approach, the team validated nearly 72 percent of the phenotype-locus associations outlined in past studies. It also tracked down 116 previously unappreciated loci linked to 45 pregnancy phenotypes, including 31 associations involving creatine, "hemolysis, elevated liver enzymes, low platelet count" (HELLP)-associated long noncoding RNA, neutrophil immune cells, and other processes that seemed to be pregnancy-specific.
"Partitioning heritability highlighted the essential roles of fetal blood, embryoid bodies, and female reproductive organs in pregnancy hematology and birth outcomes," the authors reported, noting that a subsequent pathway analysis "confirmed the complex interplay of hormone regulation, immune response, metabolism, and cell cycle processes during pregnancy."
Along with Mendelian randomization analyses aimed at untangling complex diseases that shared underlying genetic features with the pregnancy phenotypes considered, the team went on to put together an online resource known as the "PheWeb" platform.
"This resource is poised to play a pivotal role in unraveling the genetic underpinnings of maternal/postnatal-related phenotypes," authors of that study suggested, "offering valuable tools for scientists, clinicians, and users worldwide."
For another Cell Genomics study, members of the same team used data from 14,744 pregnancies in China to delve into the genetic architecture of five glycemic traits during pregnancy — from oral glucose tolerance test-related traits to gestational diabetes mellitus.
"Glycemic traits during pregnancy play a crucial role in maternal and fetal health," co-senior and co-corresponding authors Aifen Zhou, with the Tongji Medical College and Wuhan Children's Hospital, and Xin Jin, a researcher affiliated with BGI Research, the South China University of Technology, and Shanxi Medical University, and their colleagues explained. "Abnormal glycemic traits during pregnancy may indicate a risk of developing gestational diabetes, which can have adverse outcomes for both the mother and the baby."
The analyses, which again focused on women who received NIPT during pregnancy, highlighted 25 locus-trait associations. Along with associations between gestational diabetes and the CDKAL1 and MTNR1B genes, for example, the researchers identified known associations between the PCSK1 gene and fasting glucose levels, along with previously unappreciated ties between the estrogen receptor gene ESR1 and fasting glucose in pregnancy.
"Our work enhances the findings in East Asian populations and highlights the need for independent studies," the authors reported, adding that their subsequent correlation, Mendelian randomization, and transcriptome-wide association analyses "provided genetic insights into the relationship between pregnancy glycemic traits and hypertension."
More broadly, they added, "the integrative analysis of genomic and other multiomics data holds significant promise for providing a comprehensive exploration of the disease etiology of pregnancy hyperglycemia."