PhD Scientific Days 2023

Budapest, 22-23 June 2023

Mental Health Sciences - Posters M

Investigating the Association Between Polygenic Risk Score of Depression and Functional Connectivity of the Nucleus Accumbens in Healthy Individuals: Distinct Role of SIRT1

Dora Torok1,2, Kinga Gecse1,2, Angela Hammer1, Anna Nemeth1, Xenia Gonda1,2,3, Gyorgy Bagdy1,2, Peter Petschner1,2,4,5, Gabriella Juhasz1,2

1 Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary
2 NAP3.0-SE Neuropsychopharmacology Research Group, Hungarian Brain Research Program, Semmelweis University, Budapest, Hungary
3 Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest, Hungary
4 Bioinformatics Center, Institute of Chemical Research, Kyoto University, Gokasho, Uji, Kyoto, 611-0011, Japan
5 Research Unit for Realization of Sustainable Society, Kyoto University, Gokasho, Uji, Kyoto, 611-0011, Japan

Text of the abstract

Nucleus accumbens (NAc) is a key region of the reward circuit that is thought to be involved in the symptomatology of depression through its altered connectivity with other brain regions. In animal studies, decreased SIRT1 gene expression in the NAc was associated with increased vulnerability to stress-induced depression-like phenotype. In humans, less is known about the role of SIRT1 in depression and its role in the reward system. A growing number of studies consider polygenic risk scores (PRSs) behind depression but the relationship between PRS and depression-related neural circuits is still undiscovered.

Therefore, we aimed to investigate the effect of genetic risk for depression on the functional connectivity of NAc in healthy individuals.

To investigate individual-level susceptibility for depression, as a first step, we performed genome-wide association analysis in the UK Biobank database for current depression phenotype (N= 227090) using Plink2. Then, the summary statistics were used to calculate the PRS with LDPred2 on our Hungarian dataset of 102 healthy individuals who participated in a resting-state functional magnetic resonance imaging session. Seed-based resting-state connectivity analysis was conducted with NAc as the seed region. We investigated the correlation between PRS for the whole genome and restricted genetic risk of the SIRT1 gene and the functional connectivity of NAc with SPM12.

There was no significant correlation between genomic PRS and resting-state functional connectivity of NAc. However, the genetic risk of SIRT1 variants showed a significant negative correlation with the functional connectivity of NAc with the thalamus (p<0.001) and with the midcingulate cortex (p<0.001). The reported results survived correction for multiple comparisons (pFWE<0.05).

Increased genetic risk of SIRT1 variants for depression was associated with decreased functional connectivity within the reward circuit. Our results strengthen the assumption that SIRT1 is important in rewarding and motivational behaviour by affecting NAc connectivity. Since the genomic PRS for depression seems not to affect the functional connectivity of NAc in healthy individuals, thus our future aim is to capture the association of PRS and functional connectivity in a large-scale population with a depression diagnosis.

TKP2021-EGA-25, NAP2022-I-4/2022, ERAPERMED2019-108