The genetic architecture of autistic traits and negative symptoms in non-affective first-episode psychosis: an exploratory longitudinal study
Por:
Mezquida G, Perez-Ramos A, Guasch-Capella N, Forte MF, Parellada M, Amoretti S, Serra-Navarro M, Galvañ J, Cuesta MJ, Mané A, la Serna E, Mitjans M, Bioque M, García-Rizo C, Segura AG and Group AP
Publicada:
1 oct 2026
Ahead of Print:
1 may 2026
Resumen:
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(ASD)), schizophrenia (PGS(SZ)), educational attainment (PGS(EA)), and cognitive performance (PGS(CP)), 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(ASD) showed nominal associations (p < 0.05) with PAUSS-total and NSFS-total. At the subdomain level, PGS(CP) was significantly associated with PAUSScom (p = 0.019), while PGS(ASD) 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(ASD) remained associated with PAUSSrrb (p = 0.009; p.adj=0.048), but not EXP, and PGS(EA) 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.
Filiaciones:
Mezquida G:
Serra-Hunter Lecturer Fellow, Department of Clinical Foundations, Pharmacology Unit, University of Barcelona
CIBERSAM-ISCIII
Barcelona Clínic Schizophrenia Unit (BCSU), Neuroscience Institute, Hospital Clínic of Barcelona, Barcelona, Spain
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), C/Casanova 143, CP 08036, Spain
Perez-Ramos A:
Centre for Biomedical Research in Mental Health (CIBERSAM), ISCI-III, Madrid, Spain
Barcelona Clínic Schizophrenia Unit (BCSU), Neuroscience Institute, Hospital Clínic of Barcelona, Barcelona, Spain
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain, University of Cadiz, Cadiz, Spain
Guasch-Capella N:
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Barcelona Clínic Schizophrenia Unit (BCSU), Neuroscience Institute, Hospital Clínic de Barcelona, Barcelona, Spain
University of Barcelona, Medicine Department, Barcelona, Spain
Forte MF:
Bipolar and Depressive Disorders Unit, Neuroscience Institute, Hospital Clinic de Barcelona, Barcelona, Spain. Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Parellada M:
Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, IiSGM, CIBERSAM-ISCIII, School of Medicine, Universidad Complutense, Madrid, Spain
Amoretti S:
Psychiatry, Mental Health and Addictions Group, Vall d'Hebron Research Institute (VHIR), Instituto de Investigación Sanitaria Acreditado Instituto de Investigación - Hospital Universitario Vall d'Hebron (IR-HUVH), Barcelona, Catalonia, CIBERSAM-ISCIII, Spain
Serra-Navarro M:
Bipolar and Depressive Disorders Unit, Neuroscience Institute, Hospital Clinic de Barcelona, Barcelona, Spain. Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, CIBERSAM-ISCIII, Spain
Galvañ J:
Department of Psychiatry, Hospital Universitario de Navarra
Instituto de Investigación Sanitaria de Navarra (Idisna), Pamplona, Spain
Cuesta MJ:
Grup MERITT, Institut de Recerca Sant Joan de Déu. Parc Sanitari Sant Joan de Déu, CIBERSAM-ISCIII
Mané A:
Department of Child and Adolescent Psychiatry and Psychology, 2021SGR01319, Hospital Clínic de Barcelona. Fundació Clínic-IDIBAPS
CIBERSAM-ISCIII
Department of Medicine, Institute of Neuroscience, University of Barcelona, Spain
la Serna E:
Department of Genetics, Microbiology, and Statistics, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain, Biomedicine Institute of the Universitat de Barcelona (IBUB), Spain
Institut de Recerca Sant Joan de Déu (IRSJD), Esplugues de Llobregat, CIBERSAM-ISCIII, Spain
:
Barcelona Clínic Schizophrenia Unit (BCSU), Neuroscience Institute, Hospital Clínic of Barcelona, Barcelona, Spain
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain, CIBERSAM-ISCIII
Departament de Medicina, Institut de Neurociències (UBNeuro), Universitat de Barcelona
Bioque M:
Bipolar and Depressive Disorders Unit, Hospital Clínic de Barcelona
Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain
García-Rizo C:
Barcelona Clínic Schizophrenia Unit (BCSU), Neuroscience Institute, Hospital Clínic of Barcelona, Barcelona, Spain
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
CIBERSAM-ISCIII
Departament de Medicina, Institut de Neurociències (UBNeuro), Universitat de Barcelona, Barcelona, Spain
Segura AG:
Bipolar and Depressive Disorders Unit, Hospital Clínic de Barcelona
Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Catalonia, Barcelona, Spain
Group AP:
PEPs Group: A. Martínez-Pinteño, V. Llorca, J. González Peñas, L. Pina-Camacho, A. Roldán, A. González-Pinto, I. Zorrilla, P. Ruiz, C. De-la-Camara, M. J. Escartí, O. Rivero, L. Prats, C. Romans, E. Vieta, A. Martinez-Aran, J. Castro-Fornieles, I. Baeza, M. P. Portilla, R. Sagarra, A. Zabala, R. Rodriguez-Jimenez, M. A. Alvarez-Mon, J. Usall, S. Sarró, E. Pomarol-Clotet, Á. Ibáñez, A. M. Sánchez-Torres, V. Balanzá-Martínez
Open Access
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