T8. INSULIN ASSOCIATED VENTRAL TEGMENTAL AREA EXPRESSION-BASED POLYGENIC SCORE PREDICTS ADULT PSYCHIATRIC-CARDIOMETABOLIC COMORBIDITY AFTER PRENATAL ADVERSITY

Psychiatric patients exhibit elevated prevalence of obesity and cardiometabolic disorders, traits that also demonstrate substantial heritability and a potential genetic overlap in the brain. Emerging evidence indicates that prenatal adversity may sensitize midbrain reward circuits, promoting dysfunctional signaling linked to childhood impulsivity and persistent overeating, which may contribute to an increased risk of adult metabolic and psychiatric disorders. Notably, not everyone exposed to early life adversity will develop behavioral alterations or adult diseases, therefore simply using a history of adversity exposure is not enough to identify individuals at risk. Brain insulin signaling has been suggested as a mediator of the effects of prenatal adversity on neurodevelopment and behavior, with long-term consequences on physical and mental health. Since the ventral tegmental area/substantia nigra (VTA) integrates dopaminergic and metabolic signals, where insulin receptors (IR) are found on dopaminergic neurons, we propose that IR-function associated genetic variants (SNPs) in the VTA could moderate the effect on prenatal adversity on the risk for childhood impulsivity and adult metabolic-psychiatric disorders. Available rodent brain mass spectrometry data was used to identify a network of proteins binding to the IR in brain cells nuclei. Characterization of the network was performed by gene ontology terms (GO), nested cluster analysis and drug-gene interactions (DGIdb). SNPs associated to the genes from the protein network were mapped and weighted by their expression in the VTA/SN (GTEx), and then used to calculate an expression-based polygenic score (mssIR-ePRS) in two different human cohorts. We used low birth weight (LBW) as an indicator of prenatal adversity to investigate how IR-function associated genetic background influences early-life adversity associated outcomes. In the Canadian MAVAN birth cohort, infant reflective-impulsivity was assessed at 48 months using the Information Sampling Task (IST), while mental and cardiometabolic comorbidities were evaluated in adulthood within the UK Biobank cohort. We observed an enrichment of GO terms related to DNA binding, suggesting that this network captures the IR’s ability to act as a transcription factor. Nested cluster analysis identified four clusters of protein complexes, with some of the nodes being drug targets of diabetes and hypercholesterolemia related treatments. mssIR-ePRS moderated the association between LBW and reflective-impulsivity in MAVAN (βˆ= 0.17, p = .043, N=288). In which LBW was associated with high impulsivity only in participants with high mssIR-ePRS (βˆ= 0.22, p = 0.05), suggesting that mssIR-ePRS captures individual susceptibility to prenatal adversity. In adults from UK Biobank, LBW was associated with higher risk of having mental and cardio-metabolic co-morbidities especially in those with high mssIR-ePRS scores (βˆ= -0.25, p < 0.001, N=225,839). These results provide a developmental explanation to the comorbidity of psychiatric and cardiometabolic disorders, confirming that brain insulin function plays a key role in defining long-term risk for childhood behavioral alterations and adult chronic diseases. Our biologically informed polygenic score method is able to identify gene-environment interactions and may be useful in informing vulnerability.