Early-life exposure to disadvantage predicts a number of health and academic disparities. Even so, 40-60% of youth reared in disadvantaged contexts evidence resilient outcomes. Although these youth provide an important model of successful adaptation to adversity, we know relatively little about the origins of their positive outcomes, particularly the role of biological mechanisms. The current study sought to identify methylomic biomarkers of resilience in a unique sample of 135 twin pairs residing in disadvantaged neighborhoods. We conducted a Methylome Wide Association Study (MWAS) across the entire sample to uncover differentially methylated probes (DMPs) for psychiatric, academic, and social resilience, as well as resilience across domains. We uncovered methylome-wide significant DMPs for social and academic resilience and suggestive DMPs for each of the four resilience phenotypes. Pathway analyses suggested that methylation in pathways related to DNA repair and transcription and initiation of RNA Polymerase III are implicated in academic resilience while those related to T cell receptor signaling are implicated in social resilience. These analyses also highlight the role of the BRF1 gene and the HLA region in academic and social resilience, respectively. To narrow in on DMPs that were specifically environmental in origin, we then conducted twin difference analyses with the discordant MZ twin pairs for each corresponding resilience phenotype. The methylome-wide significant DMPs did not differ significantly across discordant MZ twin pairs. Our findings predominantly highlight the role of biological mechanisms in resilience, providing support for the structural organizational model of resilience.
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