Systemic interindividual epigenetic variants link periconceptional environment to human fetal development

At rare human genomic regions, DNA methylation states are established in the early embryo and maintained during cellular differentiation, yielding systemic (i.e. not tissue-specific) interindividual epigenetic variation. Previous screens for such correlated regions of systemic interindividual variation (CoRSIVs) were limited to White Americans. Here, we describe the first human CoRSIV screen including self-identified Black and White Americans. We integrate deep whole-genome bisulfite sequencing data for three tissues from each of ten Black and ten White donors in the NIH Genotype-Tissue Expression program. This approach identifies twice as many CoRSIVs among Black than White Americans. Establishment of CoRSIV methylation is sensitive to periconceptional environmental exposures including assisted reproduction, seasonal variation, and famine. CoRSIV-associated genes are enriched for GWAS variants linked to cancer and neurodevelopment. Although only 15% of Black CoRSIVs overlap with those among White individuals, both sets are associated with the same subfamilies of transposable elements. Within multiple cell lines, ranked enrichments of transcription factor binding to Black and White CoRSIVs are exquisitely coordinated and related to genome organization, indicating that CoRSIV methylation states established in the early embryo play an important role in guiding subsequent cellular differentiation.