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 x 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.

The authors have declared no competing interest.

The current work is supported by the Consortium on Individual Development (CID) and the "Aggression in Children: Unraveling gene-environment interplay to inform Treatment and InterventiON strategies" project (ACTION). CID is funded through the Gravitation Program of the Dutch Ministry of Education, Culture, and Science and the Netherlands Organization for Scientific Research (NWO grant number 024-001-003). ACTION received funding from the European Union Seventh Framework Program (FP7/2007-2013) under grant agreement no 602768. M.B. is supported by an ERC consolidator grant (WELL-BEING 771057, PI Bartels) and NWO VICI grant (VI.C.2111.054, PI Bartels). J.D. acknowledges the NWO-funded X-omics project (184.034.019) and D.I.B. the Royal Netherlands Academy of Arts and Sciences Professor Award (PAH/6635).

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Central Ethics Committee on Research Involving Human Subjects of the VU University Medical Center, Amsterdam waived ethical approval for this work.

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The standardized protocol for large-scale collection of buccal-cell (and urine) samples in the home situation as developed for the ACTION Biomarker Study in children is available at https://dx.doi.org/10.17504/protocols.io.eq2ly7qkwlx9/v1. The data of the Netherlands Twin Register (NTR) may be accessed, upon approval of the data access committee, through the NTR (https://ntr-data-request.psy.vu.nl/).