2025I087

Cannabis use and schizophrenia age at onset, from cellular models to clinical phenotypes: molecular signatures to improve early detection and prevention

A wealth of population-based and genomic research underscores the substantial heritability of schizophrenia (SZ), with genetic
influences particularly notable in early-onset cases. Additionally, it is known that various environmental factors contribute to
susceptibility to the disorder, with cannabis use being one of the most consistently described in relationship to the risk for
psychotic symptoms/disorders. In particular, exposure during adolescence has been linked to an earlier onset of psychosis and
a worse prognosis.

Despite epidemiological and clinical evidence, the nature of the relationship between cannabis use and the development of
psychosis remains largely unknown. Therefore, we propose developing a multimodal study that, through the combination of
basic and clinical approaches, provides relevant information on the molecular mechanisms of the effects of cannabis and the
identification of biomarkers with translational utility.

First, to uncover key genomic and regulatory pathways contributing to cannabis use effects in SZ, we will evaluate the neuronal
response to exposure to delta-tetrahydrocannabinol (THC, the main psychoactive component of the Cannabis sativa plant) in
cortical neurons derived (iNeurons, from induced neurons) from human induced pluripotent stem cells (hiPSCs). Our group has
established a cohort of hiPSCs from 4 patients with early-onset SZ (onset <16 years), 4 with adult-onset SZ (onset >25 years),
and 8 healthy controls, with balanced sex distribution. The hiPSC-derived iNeurons provide a robust platform to investigate
dynamic changes in human neuronal cells, enabling the identification of transcriptomic profiles associated with THC exposure
and influenced by the age of SZ onset.

One of the key mechanisms in SZ is the alteration of synaptic function, related to the localization and expression of messenger
RNA (mRNA) in synapses. The transport of mRNAs from the soma to neurites depends on assembly into condensates.
Preliminary data from our group indicate that genetic variants associated with SZ are enriched in genes encoding mRNAs
localized in neurites. Therefore, separately analyzing the somatic and neuritic fractions of iNeurons will allow us to identify
specific expression changes and study how mRNA transport influences the relationship between THC exposure and SZ age of
onset (transcriptomic signatures). These changes will allow the definition of the related gene-sets which will be used to estimate polygenic risk scores for SZ (genomic profiles).

Second, in a new sample of patients (20 with early-onset SZ and 20 with adult-onset SZ, with a balanced distribution in terms of cannabis use and sex), we will analyze the impact of the identified genomic and transcriptomic profiles of THC exposure on the clinical phenotypes of this new cohort. That is, based on data provided by the iNeurons model, we will assess the clinical
validity of the identified molecular profiles, hoping to identify genetic/expression biomarkers associated with age of onset and
cannabis use.

Third, we will investigate how the molecular profiles of cannabis exposure, previously identified, relate to psychosis
predisposition in a sample of 875 young adults assessed for cannabis use and psychotic experiences. This sample already has
genetic data that allow the calculation of polygenic risk scores (PRS) for SZ, focusing on THC-modulated genes in iNeurons.
We will analyze the interaction between these PRS and cannabis use to identify specific patterns of genetic and environmental
predisposition to psychosis.

114.232,00 €

Ministerio de Sanidad - Plan Nacional Sobre Drogas

Financiado por la Delegación del Gobierno para el Plan nacional sobre Drogas

Enlace al Portal del Plan Nacional sobre Drogas - proyectos de investigación