Earlier Schizophrenia Age of Onset Linked to Increased Genetic Copy Number Variants: Researcher Insights

Researchers identified a link between age of onset in schizophrenia and increased burden of genetic structural modifications, specifically copy number variants (CNVs); the number of deletions was found to be significantly associated with earlier disease onset.^1,2 Patients with younger onset of schizophrenia were found to have the highest CNV load, with a strong trend of later onset with decreasing CNV burden.

Investigators highlighted that “the identification of deletion burden as a modulator of [age of onset] may have important translational implications in the future,” noting the result “supports the potential for genetic stratification of [schizophrenia] patients based on CNV profiles, which could eventually inform more personalized treatment strategies” and may “provide a biological framework for genetic counseling, particularly for families with a history of early-onset psychosis.”¹

Lead researcher Gerard Muntane Medina, PhD, shared more on the clinical implications of the study with Psychiatric Times.

Psychiatric Times: It is well-established that CNVs contribute to a patient’s risk of schizophrenia, but why was it important to investigate CNVs as modulating disease age of onset?³

Gerard Muntane Medina, PhD: A few years ago, we conducted a genome-wide association study on age at onset of schizophrenia and found that common genetic variants contribute to when the disease manifests. Building on this, we wanted to investigate whether rare structural variants, specifically CNVs, might also play a role.

Prior evidence suggests that individuals carrying CNVs often experience more severe forms of schizophrenia, and earlier-onset cases are also known to have a more severe clinical course. This led us to hypothesize that CNV burden could influence not only disease risk, but also the timing of onset. Given our access to a well-characterized dataset, we were well placed to test this hypothesis directly.

PT: Of your findings, what would you highlight for the practicing clinician?

Muntane Medina: The key finding of our study is that the burden of genomic deletions—rather than duplications—is significantly associated with an earlier age at onset of schizophrenia. In other words, individuals carrying a higher number of deletions tend to develop the disorder at a younger age.

Importantly, this association was consistent when age at onset was analyzed as a continuous variable and remained robust across multiple sensitivity and quality-control analyses. This suggests that not all types of structural variation contribute equally to development of schizophrenia, highlighting a more specific role for deletions in modulating disease timing.

PT: If CNV deletions specifically can contribute to earlier onset, what implications do CNVs have in neurodevelopment generally?

Muntane Medina: All individuals carry some level of structural variation in their genomes, including deletions. However, deletions are more likely than duplications to disrupt gene function, particularly when they remove coding regions or regulatory elements. This makes them more likely to have a direct biological impact.

Our finding that deletion burden is associated with earlier onset suggests that these variants may influence neurodevelopmental processes that are critical in the early stages of the disorder. In this sense, deletions could be contributing to a greater biological vulnerability that manifests as an earlier clinical presentation.

Importantly, this helps refine our understanding of genetic risk in schizophrenia—not all variants act in the same way, and distinguishing between different types of structural variation can provide more precise insights into disease mechanisms.

PT: Might clinicians be able to use genetic measures for treatment or diagnosis of schizophrenia in the future?

Muntane Medina: At this stage, the findings are primarily informative at the population level and do not yet translate into direct clinical applications. However, in the future, it may become possible to incorporate measures of genomic burden—such as the number of deletions an individual carries—into broader risk stratification frameworks.

It is important to emphasize that carrying a small number of deletions is common and not inherently problematic. However, a higher burden of deletions, particularly those affecting relevant genes, could contribute to overall vulnerability for schizophrenia and might eventually help identify individuals at higher risk of earlier onset when combined with other genetic and clinical factors.

Ultimately, these findings represent a step toward more refined, biologically informed models of schizophrenia, although further research and replication are needed before any clinical implementation.

PT: What can clinicians take away from these genetics-focused early findings?

Muntane Medina: Clinicians should be aware that genetic factors may influence not only the risk of developing schizophrenia but also the age at which the disorder presents. Our findings suggest that structural genetic variation—particularly the burden of deletions—may contribute to earlier onset at a population level.

That said, these effects are modest and not currently useful for individual prediction in clinical practice. Rather, they add to a growing body of evidence that schizophrenia is shaped by multiple layers of genetic risk, some of which may also influence disease trajectory and timing.

Dr Muntane Medina is a research scientist at the Institut Recerca Biomèdica Catalunya Sud and assistant professor at the Universitat Rovira i Virgili and Universitat Pompeu Fabra, specializing in evolutionary and psychiatric genomics. His work focuses on integrating multi-omics data to understand the molecular mechanisms underlying neuropsychiatric disorders.

References

1. Muntane G, Valle A, Ramon-Canellas P, et al. The impact of CNV burden on age at onset of schizophrenia. Schiz Res. 2026;291:12-19

2. Rees E, Kendall K, Pardiñas AF, et al. Analysis of intellectual disability copy number variants for association with schizophrenia. JAMA Psychiatry. 2016;73(9):963-969.

3. Trubetskoy V, Pardinas AF, Qi T, et al. Mapping genomic loci implicates genes and synaptic biology in schizophrenia. Nature. 2022;604:502-508.