Abstract
Autistic traits and negative symptoms (NS) frequently co-occur in schizophrenia spectrum disorders (SSD), even in early stages such as first-episode psychosis (FEP), complicating both diagnosis and prognosis, as these dimensions strongly influence functional outcomes and may share etiological mechanisms. This study aims to explore the genetic architecture underlying autistic and NS dimensions, to support early stratification and personalised interventions. 203 non-affective FEP were analysed. Symptom severity was assessed using Positive and Negative Symptom Syndrome (PANSS) derived measures: PANSS-Autism Severity Score (PAUSS) for autistic traits and Marder-factors for NS (NSFS), including subdomains of social reciprocity, communication, restricted-repetitive behaviours (PAUSSsoc, PAUSScom, PAUSSrrb), and expressive deficits (EXP) and motivational/pleasure deficits (MAP). Polygenic scores (PGS) for autism spectrum disorder (PGS), schizophrenia (PGS), educational attainment (PGS), and cognitive performance (PGS), including pathway-specific PGS (pPGS) targeting neurodevelopmental and immune-related processes, were used to examine associations with baseline and one-year autistic and NS dimensions. At baseline, PGS showed nominal associations (p < 0.05) with PAUSS-total and NSFS-total. At the subdomain level, PGS was significantly associated with PAUSScom (p = 0.019), while PGS showed significant associations with PAUSSsoc (p = 0.034), PAUSSrrb (p = 0.009, p.adj=0.038) and EXP (p = 0.044). At one-year follow-up, PGS remained associated with PAUSSrrb (p = 0.009; p.adj=0.048), but not EXP, and PGS with PAUSScom (p = 0.023). pPGS analyses showed nominal associations (p < 0.05) between neurodevelopmental and immune pathways and PAUSSrrb, PAUSScom, and EXP. Autistic traits and NS in FEP exhibit marked multidimensionality, with distinct subdomains showing differential genetic underpinnings. Neurodevelopmental and immune-mediated pathways appear particularly relevant to restricted-repetitive traits and expressive deficits, supporting subdomain-level phenotyping as a valuable tool for early patient stratification and for refining the clinical characterisation of SSD.
![isciii[1]](https://fidmag.org/ca/img/0-60-ESCALA/isciii1.png "isciii[1]")
