Longitudinal Genome-Wide Study Reveals Genetic Architecture of Resilience Using a Novel Phenotype

The biological mechanisms underlying resilience have been extensively studied, yet our understanding of the genetic architecture of resilience in humans remains limited. While earlier genetic studies of resilience investigated effects of specific candidate genes, small sample sizes and the narrow focus on one target gene provided a limited perspective on genetic architecture. Genome-wide association studies (GWAS) can overcome these issues but have been rarely applied to resilience. To date, only two GWAS are reported, because few sufficiently large-scale datasets have a measure of resilience, and those that do may not have genetic data. Here we used a novel longitudinal resilience phenotype with genomic data from the Avon Longitudinal Study on Parent and Children (ALSPAC) to establish resilience trajectories in response to adverse childhood experiences (ACEs). Our results identify the SMARCA2 and OPRM1 genes as significant genetic markers, highlighting their roles in epigenetic mechanisms and dendritic functions associated with resilience. Post-GWAS analyses revealed enrichment of genes linked to dendritic and axonal functions, supporting the hypothesis that dendritic spine plasticity is crucial for cognitive resilience. Our approach offers novel functional insights into how resilience across early life is underpinned by genetic factors, emphasising the importance of dynamic, longitudinal phenotyping.