Intergenerational transmission of complex traits and the offspring methylome

The genetic makeup of parents can directly or indirectly affect their offspring phenome through genetic transmission or via the environment that is influenced by parental heritable traits. Our understanding of the mechanisms by which indirect genetic effects operate is limited. Here, we hypothesize that one mechanism is via the offspring methylome. To test this hypothesis polygenic scores (PGSs) for schizophrenia, smoking initiation, educational attainment (EA), social deprivation, body mass index (BMI), and height were analyzed in a cohort of 1,528 offspring and their parents (51.5% boys, mean [ SD ] age = 10 [2.8] years). We modelled parent and offspring PGSs on offspring DNA methylation, accounting for the own PGS of offspring, and found significant associations between parental PGSs for schizophrenia, EA, BMI, and height, and offspring methylation sites, comprising 16, 2, 1, and 6 sites, respectively (alpha = 2.7 × 10 ⁻⁵ ). More DNA methylation sites were associated with maternal than paternal PGSs, possibly reflecting the maternal pre- or periconceptional environment during critical embryonic development.