Integrating polygenic risk scores and brain imaging data: investigating the link between genetic risk for depression and nucleus accumbens connectivity

The Nucleus Accumbens (NAc) is a critical component of the reward circuit, believed to play a role in depression by exhibiting altered connectivity with other brain regions. Studies on animals have indicated that reduced expression of the SIRT1 gene in the NAc is associated with increased susceptibility to stress-induced depression-like symptoms. However, limited knowledge exists regarding the involvement of SIRT1 in depression and its impact on the reward system in humans. While several studies have explored the polygenic risk scores (PRSs) associated with depression, the relationship between these scores and depression-related neural circuits remains largely unknown. Hence, our objective was to investigate the influence of genetic risk for depression on the functional connectivity of the NAc in healthy individuals. To assess individual susceptibility to depression, we initially conducted a genome-wide association analysis on the UK Biobank database, focusing on the current depression phenotype (N = 227,090) using Plink2. Subsequently, we employed the summary statistics obtained from this analysis to calculate the PRS using LDPred2 on our Hungarian dataset comprising 102 healthy participants who underwent resting-state functional magnetic resonance imaging. Seed-based resting-state connectivity analysis was then performed, with the NAc serving as the seed region. Our aim was to examine the correlation between PRS calculated for the whole genome and the specific genetic risk associated with the SIRT1 gene and the functional connectivity of the NAc using SPM12. We controlled for confounding factors such as age, sex, and motion-related signal components during our analysis. Our findings did not reveal any significant correlation between genomic PRS and resting-state functional connectivity of the NAc. However, we observed a significant negative correlation between the genetic risk associated with SIRT1 variants and the functional connectivity of the NAc with the thalamus (p < 0.001) and the midcingulate cortex (p < 0.001). Importantly, these results remained significant even after correcting for multiple comparisons (pFWE < 0.05). In our pilot study, we found that an increased genetic risk of SIRT1 variants for depression was linked to reduced functional connectivity within the reward circuit. These results support the notion that SIRT1 plays a crucial role in modulating rewarding and motivational behaviors by affecting the connectivity of the NAc. While the genomic PRS for depression did not appear to influence the functional connectivity of the NAc in healthy individuals, our future objective is to investigate the association between PRS and functional connectivity on a larger scale, encompassing a population diagnosed with depression. Overall, our study contributes to the translation of findings from animal studies to humans, enhancing our understanding of the relationship between the reward system, depression, and polygenic risk score. This study was supported by the following fundings: 2017-1.2.1-NKP-2017-00002, NAP2022-I-4/2022, K143391, 2019-2.1.7-ERA-NET-2020-00005, TKP2021-EGA-25