Rethinking cognitive deficits and schizophrenia risk through genetic insights

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 of Cardiff University's Centre for Neuropsychiatric Genetics and Genomics present evidence that challenges conventional wisdom about cognitive deficits in schizophrenia. Their analysis reveals that premorbid cognitive impairment – lower IQ and other cognitive deficits present before the onset of psychosis – is largely explained by non-familial factors rather than by the same inherited genetic variants that increase risk for schizophrenia itself.

For decades, we've 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 suggests this isn't the case. Instead, it appears that neurodevelopmental disruptions are responsible for both the cognitive deficits and the increased risk of developing schizophrenia."

Professor Michael Owen

Key findings from the review include:

1. Premorbid cognitive impairment marks the presence of an underlying disruption of neurodevelopment that increases risk for schizophrenia, but cognitive impairment is not in itself causal for schizophrenia.
2. The degree 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 disturbance that increases schizophrenia risk than is absolute cognitive ability.
3. The neurodevelopmental disturbance does not appear to be primarily caused by the same familial factors, including inherited common genetic variants, that increase schizophrenia risk or that typically influence cognitive ability in the general population. Instead, rare genetic variants including copy number variations (CNVs) and damaging coding mutations that occur as new or de novo mutations contribute, as do other non-familial environmental risk factors.
4. There is evidence for 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 genetic risk for neurodegenerative disorders.

The researchers propose a model in which neurodevelopmental perturbations, largely influenced by non-familial factors, lead to both cognitive impairment and increased vulnerability to schizophrenia. They also challenge the idea of a distinct "neurodevelopmental subtype" of schizophrenia, instead suggesting a spectrum of neurodevelopmental impairment across the disorder.

"These findings have important implications for how we think about schizophrenia and cognitive impairment," said Professor O'Donovan. "Understanding the causes of early neurodevelopmental disruptions will be important for developing interventions aimed at preventing or mitigating both the cognitive deficits and schizophrenia risk."

The research also highlights the need for further investigation into the causes of cognitive decline after schizophrenia onset, as well as the increased risk of dementia in this population. Understanding these processes could lead to new approaches for preserving cognitive function in individuals with schizophrenia throughout their lives.

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 may ultimately inform the development of new prevention and treatment strategies.

The full review, titled "The genetics of cognition in schizophrenia," was published on 16 July 2024 and is available online at the website of Genomic Psychiatry: https://gp.genomicpress.com/aop/.