Insulin moderates the effects of early life adversity on executive functioning in a sex-specific manner

Background Early life adversity (ELA) is associated with altered insulin signaling and altered EF behaviors, in a potentially sex-specific manner. Considering the high co-morbidity between altered metabolism and executive function (EF) problems, we hypothesized that the genetic background associated with altered fasting insulin (FI) and EF could be shared Methods Our study used conjunctional false discovery rate (ConjFDR) to identify the shared genetic architecture between FI and two EFs: impulsivity and attention deficit-hyperactivity disorder (ADHD). We identified the polygenic risk score (PRS) threshold from a FI genome-wide association study (GWAS) that best predicted insulin levels in male and female ALSPAC children [N males =1,901, N females =1,834; p t-intial-males = 0.05 (11,121 SNPs), p t-intial-females = 0.15 (27,202 SNPs)], further refining it to only include SNPs significantly associated with insulin levels in children [N SNP-males = 635 SNPs, N SNP-females = 1,449 SNPs]. A phenome-wide association study (PheWAS) was also run to identify EFs associated with the interaction between the refined PRS (rPRS) and early adversity. To investigate the presence of a direct causal relationship between FI and impulsivity in the presence of adversity, we applied mendelian randomization (MR) Results ConjFDR suggested that environmental factors could be involved in the association between insulin and EFs, as there was no shared genetic background. PheWAS highlighted impulsivity and attention-related outcomes in interaction models between FI rPRS and early adversity. Finally, two-sample MR suggested a causal association between higher fasting insulin levels and impulsive behavior, specifically in females exposed to adversity (p < 0.001). Overall, a sex-specific impulsivity GWAS demonstrated that MYT1L and TSSC1 , genes that are associated with motor impulsivity, were enriched only in females. Conclusions Our study solidifies the evidence that the relationship between high FI and EF is not direct, but rather interacting with ELA exposure, especially in females. Key points Early life adversity is associated with alterations in insulin signaling and executive functioning behaviors. We report a causal association between high fasting insulin and increased impulsivity in females exposed to adversity. Our findings also support the idea that fasting insulin moderates the long-term effects of early life adversity on executive functions in females. This research provides insights into the mechanisms by which insulin moderates the effects of early life adversity on executive function disorders and informs the development of potential interventions.