370. ASSOCIATIONS OF POLYGENIC RISK SCORES DIFFERENTIATING ATTENTION-DEFICIT HYPERACTIVITY DISORDER FROM AUTISM SPECTRUM DISORDER WITH COGNITIVE AND CORTICAL ALTERATIONS IN SCHIZOPHRENIA PATIENTS

Abstract Background Schizophrenia (SCZ) is a clinically and genetically heterogeneous disorder that shares genetic factors with autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD). A genome-wide association study (GWAS) differentiating ADHD from ASD was performed recently. Although genetic correlations of regional cortical structures with the risk of SCZ, ASD, and ADHD have been identified, no study has yet investigated the genetic correlations between the genetic factor differentiating ADHD from ASD and brain cortical structures or whether this genetic factor influences cognitive functions and brain cortical structures in patients with SCZ. Aims & Objectives Given the clinical and genetic heterogeneity of SCZ and its significant overlap with ASD and ADHD, our study focuses specifically on SCZ to better understand the distinct genetic contributions to cognitive impairments and cortical abnormalities within this population. By isolating SCZ as the primary condition, we aim to elucidate the unique and shared genetic underpinnings that differentiate it from other neurodevelopmental disorders. The significance of this study lies in its potential to unravel the specific genetic influences on cognitive impairments and cortical abnormalities in SCZ. By exploring the polygenic risk scores (PRSs) differentiating ADHD from ASD, we aim to contribute to the understanding of the genetic architecture that impacts cognitive functions and brain structures in SCZ. This could lead to more precise diagnostic tools and personalized treatment strategies, ultimately improving outcomes for individuals with SCZ. Method Based on the GWAS data (9,315 ASD and 11,964 ADHD patients), PRSs differentiating ADHD from ASD (indicating a greater risk of ADHD and a lower risk of ASD) were calculated for SCZ patients (n=168). Cognitive performance, including verbal comprehension (VC), perceptual organization (PO), working memory (WM), and processing speed (PS), was assessed using the WAIS-III (n=145). The surface areas and cortical thicknesses of 34 bilateral brain regions were extracted using FreeSurfer (n=126). We examined the associations of these PRSs with cognitive performance and cortical structures in SCZ patients. Results Among the four cognitive domains, a higher PRS, indicating a greater risk of ADHD, was associated with impaired WM in SCZ patients (beta=-0.21, p=0.012). A lower PRS, indicating a greater risk of ASD, was associated with decreased surface areas of the left medial orbitofrontal (beta=0.21, p=8.29×10-4), left entorhinal (beta=0.21, p=0.025), left postcentral (beta=0.18, p=7.52×10-3), right fusiform (beta = 0.17, p = 6.64×10-3), and left fusiform cortices (beta=0.17, p=7.77×10-3) in SCZ patients. A higher PRS, indicating a greater risk of ADHD, was associated with decreased cortical thickness in the bilateral transverse temporal regions (left, beta=-0.17, p=0.039; right, beta=-0.17, p=0.045). Discussion & Conclusions Our study revealed a relationship between genetic factors that differentiate ADHD patients from ASD patients and both cortical structure and cognitive performance in SCZ patients. These findings suggest that the heterogeneity of SCZ might be partly derived from genetic factors related to neurodevelopmental and psychiatric disorders other than SCZ.