Is Impulsivity Simply a Failure of Self-Control? Evidence Based on Multi-omics analyses of Genomics, Metabolomics and Brain imaging

• First study to disentangle impulsivity and self-control through multi-modal evidence spanning brain imaging, genetic, and metabolic phenotypes. • Self-control was primarily linked to functional organization in the frontal lobe, whereas impulsivity was associated with subcortical reward-related regions. • The gene HP1BP3 showed a unique association with impulsivity, but not with self-control. • Arginine and proline metabolism emerged as a shared biochemical pathway implicated in both impulsivity and self-control. High impulsivity—a hallmark of various adverse life outcomes such as substance abuse, impulsive buying, violence, and crime—has typically been considered as a failure of self-control. However, is impulsivity simply a failure of self-control? To address this issue, we employed multi-omics combined with brain imaging approach in a large-scale sample ( N brain imaging =1524, N genomics =835, N metabolomics =946) to elucidate the relationship between impulsivity and self-control. Mendelian randomization showed a bidirectional association between impulsivity and self-control, suggesting that they influenced each other. Partial least squares analysis highlighted that self-control primarily implicates the frontal lobe regions (e.g., superior frontal gyrus), whereas impulsivity involves the amygdala, insula, and basal ganglia. The cerebellum, superior frontal gyrus, and middle frontal gyrus were identified as shared areas in impulsivity and self-control. Furthermore, gene-based association analysis identified heterochromatin protein 1 binding protein 3 as specifically related to impulsivity, while pathway enrichment analysis demonstrated that arginine and proline metabolism was a common metabolic pathway associated with both impulsivity and self-control. Overall findings demonstrate that impulsivity and self-control involve both shared and distinct brain regions, genetic and metabolic foundations. The brain imaging results suggest that impulsivity is related not only to self-control-related processes but also to the motivation to pursue rewards. Together, this large-scale integrative study firstly provides a side-by-side map of genomic, metabolic, and limbic-network signatures of impulsivity distinct from self-control, offering a foundation for mechanism-driven biomarker and intervention research in maladaptive impulsivity.