In a comprehensive review of recent genetic and population studies published in the peer-reviewed medical journal Genomic psychiatry (Genomic Press, New York), Professors Michael Owen and Michael O’Donovan from Cardiff University’s Center for Neuropsychiatric Genetics and Genomics present evidence that challenges the conventional wisdom about cognitive deficits in schizophrenia. Their analysis shows that premorbid cognitive impairment – lower IQ and other cognitive deficits that were present before the onset of psychosis – is largely explained by non-familial factors rather than by the same inherited genetic variants that increase the risk of schizophrenia itself.
For decades, we have assumed that premorbid cognitive problems in people with schizophrenia were directly caused by the same genetic factors that cause the disorder. Our review of the latest research shows that this is not the case. Instead, it appears that disturbances in neurodevelopment are responsible for both the cognitive deficits and the increased risk of developing schizophrenia.”
Professor Michael Owen
Key findings from the evaluation include:
- Premorbid cognitive impairment indicates the presence of an underlying disturbance in neurodevelopment that increases the risk of schizophrenia, but cognitive impairment in itself is not causal for schizophrenia.
- The extent to which an individual’s cognitive ability deviates from what would be expected based on family history is a better predictor of the underlying neurodevelopmental disorder that increases the risk of schizophrenia than absolute cognitive ability.
- The neurodevelopmental disorder does not appear to be primarily caused by the same familial factors, including inherited genetic variants, that increase the risk of schizophrenia or that typically affect cognitive abilities in the general population. Instead, rare genetic variants, including copy number variations (CNVs) and deleterious coding mutations, occur as new or the new one mutations contribute to this, as do other non-familial environmental risk factors.
- There is evidence of further cognitive decline after diagnosis in some individuals, as well as an increased risk of dementia, but this does not appear to be substantially related to the genetic risk of neurodegenerative disorders.
The researchers propose a model in which disruptions in neurodevelopment, largely influenced by non-familial factors, lead to both cognitive impairment and increased vulnerability to schizophrenia. They also challenge the idea of a separate ‘neurodevelopmental subtype’ of schizophrenia, instead suggesting a spectrum of neurodevelopmental disorders within the entire disorder.
“These findings have important implications for the way we think about schizophrenia and cognitive disorders,” says Professor O’Donovan. “Understanding the causes of early disturbances in neurodevelopment will be important for developing interventions aimed at preventing or reducing both the cognitive deficits and the risk of schizophrenia.”
The study also highlights the need for further research into the causes of cognitive decline after the onset of schizophrenia, as well as the increased risk of dementia in this population. Understanding these processes could lead to new approaches for maintaining cognitive function in people with schizophrenia across the lifespan.
This review represents a significant advance in our understanding of the complex interplay between genetics, cognition, and schizophrenia risk. It paves the way for more targeted research into the underlying mechanisms of cognitive impairment in schizophrenia and can ultimately serve as a source of inspiration for the development of new prevention and treatment strategies.
The full review, entitled ‘The genetics of cognition in schizophrenia’, was published on July 16, 2024 and is available online at the website of Genomic psychiatry: https://gp.genomicpress.com/aop/.