Sex-linked placental DNA methylation associated with early-onset preeclampsia

Background Impaired placentation and placental dysfunction are drivers of early-onset preeclampsia (EOPE), yet our understanding of the molecular changes underlying the placental pathology is incomplete. DNA methylation (DNAme) is one tool that has been used to identify molecular patterns associated with EOPE; however previous studies have only examined EOPE-associated DNAme on the autosomes. This is the first study to identify sex chromosome associated EOPE DNAme. Methods DNAme array data (450K and EPICv1 arrays) from 843 placentas (XX = 386, XY = 457) from public datasets were analysed. We identified X and Y chromosome DNAme differences between EOPE ( n = 63) and non-preeclamptic preterm births ( n = 71). We also identified sex chromosome DNAme associated with eoPRED score, a DNAme -based score of EOPE-associated placental pathology, using all samples ( n = 843). Linear modelling for sex chromosomal DNAme was sex-stratified, and an interaction test was used to determine if significant results were sex-specific. Results We identified numerous sex-linked differentially methylated cytosines (DMCs) with EOPE in the individual datasets/array platforms and 15 high-confidence and high-effect associations that were present across array platforms. There were more X chromosome EOPE DMCs identified in XY than XX samples, yet most associations were not sex-specific after testing for an interaction with sex. We observed similar associations whether the clinical diagnosis of EOPE or eoPRED score were used; however, we identified more DMCs using eoPRED score. Conclusions This is the first study to evaluate placental DNAme on the X and Y chromosomes in EOPE. We observe significant findings on the sex chromosomes including genes such as ACE2 , MBLN3 , and MIR503HG which may have relevance to the pathophysiology of EOPE.