The interactive effects of polygenic risk scores and single gene disorders on the subcortical structure

Polygenic Risk Scores (PRS) represent a weighted sum of the number of risk alleles an individual carries for developing a particular disease. Recent studies have revealed interactive effects of PRS and rare copy number variants (CNV) previously associated with risk for psychiatric disorders. There is less information about the interaction of PRS and genetic disorders caused by pathogenic variants in a single gene. Noonan Syndrome (NS) is a neurogenetic syndrome caused by germline mutations encoding components of the Ras/mitogen-activated protein kinase pathway. In most cases (³50%), NS is caused by the mutation in PTPN11. In recent studies, our group found that the NS phenotype is characterized by physical and behavioral problems, including impairments in executive function and social cognition and a high prevalence of ADHD and ASD symptoms. We also found that children with NS have smaller volumes in subcortical brain structures than healthy controls, especially of the striatum. Our aim is to calculate the PRS of children with NS and, in addition, examine the subcortical volumes in NS and their association with PRS. Anatomical MRI scans were acquired from 119 children, 57 children with NS, and 62 matched healthy controls (HC, aged range: 4-14 years). Fourteen subcortical structures were included after segmentation, for each subcortical structure, volumes were calculated and compared to healthy controls (HC). ADHD PRS were calculated for 15 NS participants. The correlation between subcortical volumes and ADHD PRS for each participant were examined. In line with previous studies, we found that subcortical structures were significantly smaller in individuals with NS compared to HC, specifically the striatum (p range= 0.01-0.00001). ADHD PRS of children with NS ranged between 0.20 -0.25. We found a positive correlation between ADHD PRS and accumbens volume (r=0.57, p=0.025) after correcting for age, sex, and total brain volume. There were other notable positive correlations with ADHD PRS, like the volume of the amygdala (r=0.40, p= 0.13), caudate (r=0.40, p=0.13), and thalamus (r=0.39, p=0.14), but did not achieve significance. We found significant differences in subcortical volumes of children with NS versus HC and significant correlations between ADHD PRS scores and NS subcortical volumes. The results of this study demonstrate the effect of NS mutation and the interaction between PRS and NS gene in the brain structure. We expect to expand our PRS sample in the future to understand these interactions better.