A new study from researchers at King's College London has split schizophrenia risk into two genetically distinct pathways. One characterised by shared genetic risk with bipolar disorder and associated with higher educational attainment and another unique to schizophrenia itself, associated with lower educational attainment and poorer cognition.
The research, which was published in Molecular Psychiatry and funded by the National Institute for Health and Care Research (NIHR) Maudsley Biomedical Research Centre, helps resolve a long-standing paradox in psychiatric genetics. Previous studies have appeared contradictory, showing that a genetic predisposition to schizophrenia is linked to lower intelligence (IQ), but higher educational attainment.
To investigate this, the team at the Institute of Psychiatry, Psychology & Neuroscience used an advanced statistical technique called genomic structural equation modelling. This new approach has allowed them to separate the genetic influences shared between schizophrenia and bipolar disorder from those specific to schizophrenia. In simple terms, they "subtracted" the genetic effects linked to bipolar disorder from those seen in schizophrenia, leaving behind the genetic component unique to schizophrenia. The same technique was also used in another new King's-led research publication, also funded by the NIHR Maudsley BRC, which identified the genetic blueprint of mania in bipolar disorder.
Using this approach, the researchers identified 78 genetic variants associated with both schizophrenia and bipolar disorder, and 63 variants specific to schizophrenia.
They found that the schizophrenia-specific genetic variants are linked to lower educational attainment (based on the highest qualification level achieved) and lower IQ (measured via a touchscreen questionnaire). In contrast, the genetic variants that schizophrenia shares with bipolar disorder are linked to higher educational attainment, with minimal effect on IQ.
This was confirmed by analysing polygenic risk scores in more than 380,000 people from the UK Biobank, a measure that adds up the small effects of many genetic variants to estimate an individual's overall genetic risk for a trait.
The findings provide early evidence for two distinct genetic routes to schizophrenia:
- One pathway shared with bipolar disorder and linked to better educational outcomes.
- One pathway unique to schizophrenia and linked to poorer cognitive and educational outcomes.
This suggests that the positive association between schizophrenia genetic risk and educational attainment is driven largely by its overlap with bipolar disorder. In contrast, the genetic risk unique to schizophrenia may be more detrimental to educational attainment and IQ.
We know that schizophrenia and bipolar disorder share a considerable genetic overlap and that many people with these conditions can present with similar symptoms. People with schizophrenia, however, typically have more cognitive difficulties than those with bipolar disorder. Our study has harnessed the latest advances in genetics to shed some light on the biological drivers of these differences.
Dr Cameron Watson, Medical Research Council Clinical Research Training Fellow, King's College London and first author of the study
These findings highlight that the genetics of schizophrenia are more complex than we once thought. Two people with the same diagnosis can have very different cognitive and educational outcomes. We already know that the environment influences these differences, but our study provides evidence for the relevance of distinct genetic signatures. Current diagnostic criteria can obscure distinct biological pathways; understanding them could eventually help us refine how we diagnose and treat psychotic disorders.
Dr Evangelos Vassos, Clinical Reader at King's College London and senior author of the study
"Splitting schizophrenia: divergent cognitive and educational outcomes revealed by genomic structural equation modelling" (Cameron Watson, Johan Zvrskovec, Giuseppe Merola, Lachlan Gilchrist, Senta Haussler, Miryam Schattner, Chris Lo, Gerome Breen, Robin Murray, Cathryn Lewis and Evangelos Vassos) was published in Molecular Psychiatry. DOI: 10.1038/s41380-026-03444-3
