The Causal Relationship Between Cognitive Deficit and Risk of Schizophrenia
In this section
Polygenic risk score increases schizophrenia liability through cognition-relevant pathways
Cognitive deficits have been reliably linked with inherited risk for schizophrenia. However, studies have rarely demonstrated the direction of causality. Understanding the causal pathway would help to identify whether cognitive deficit is an intermediate phenotype on the causal path to schizophrenia, with implications for diagnosis, prediction and intervention.
This study applied bivariate and trivariate causal modelling to assess 1313 members of 1078 families; 416 with schizophrenia, 290 unaffected siblings and 607 controls. Polygenic risk score (PRS) for schizophrenia was used in modelling to represent the measure of cumulative genetic risk.
Bivariate modelling supported a causal pathway from cognition to schizophrenia liability. Results indicated that 46% of variance in schizophrenia liability is explained by variation in cognition. Trivariate modelling also showed that PRS may contribute to schizophrenia liability through cognitive deficits. Results suggested that 8.07% of variation in schizophrenia can be explained by PRS, with 2.71% of this mediated through cognitive deficit. However, the authors hypothesised that cognitive deficit may mediate an even greater genetic influence on schizophrenia, outside of what is captured by the PRS model. Indeed, it was suggested that 26.87% of causal genetic variance may not be captured by PRS modelling.
Findings from this study indicate that cognitive deficit is present in the causative chain between genetic risk and schizophrenia. Up to 33.51% of the overall heritable liability for schizophrenia may be mediated through influences on cognition. The authors suggested two proposals for this, recognising that it was unlikely that cognitive deficit directly causes psychotic symptoms. One was that poor cognition may reduce a patient’s ability to combat symptoms. Alternatively, poor cognition may be an element of the altered developmental pathway which later leads to psychosis-related neural functions.
While causal modelling does evaluate the consistency of various models to the data, the authors noted that it does not provide absolute proof of causality. Longitudinal research which assesses participants from before the onset of schizophrenia, may be more definitive. This is a key opportunity for future research, to better understand the extent to which genetic risk for schizophrenia is mediated through cognition. In addition, with 65% of genetic influences on schizophrenia not relating to cognition and PRS, other intermediate phenotypes should be investigated.
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