HMN 2026: How schizophrenia genetic risk splits into two pathways, one shared with bipolar disorder

A new study by researchers at King’s College London has split schizophrenia risk into two genetically distinct pathways. One is characterized by a shared genetic risk with bipolar disorder and associated with higher educational attainment, and another is unique to schizophrenia itself, associated with lower educational attainment and poorer cognition.

The research, which was published in Molecular Psychiatry, 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 modeling. 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, 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 analyzing 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:

1. One pathway shared with bipolar disorder and linked to better educational outcomes.
2. 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.

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