Placental DNA methylation captures shared and trait-specific genetic susceptibility across complex health conditions

The Developmental Origins of Health and Disease (DOHaD) hypothesis proposes that the perinatal environment shapes susceptibility to complex traits across life [1]. The placenta, a transient organ mediating maternal-fetal exchange, plays a central role in this process and has emerged as a key molecular archive in utero [2-4]. Placental DNA methylation (DNAm) is a unique mediator between prenatal exposures, fetal genetics and later-life outcomes [5-9]. DNAm quantitative trait loci (mQTL) have helped disentangling causal mechanisms underlying GWAS loci for complex diseases [10-15]. Despite growing evidence that placental genomic regulation has broad and profound effects on the developmental programming of early- and later-life health outcomes [17], existing placental studies remain limited in scale and largely focused on growth- and neuro-related traits [12-16]. Here, we construct a high-resolution placental mQTL resource and systematically investigate how placental DNAm relates to early- and later-life traits, and to shared vulnerability and complex interactions among them.