IQ and schizophrenia in a Swedish national sample: their causal relationship and the interaction of IQ with genetic risk

Abstract

Objective: The authors sought to clarify the relationship between IQ and subsequent risk for schizophrenia.

Method: IQ was assessed at ages 18-20 in 1,204,983 Swedish males born between 1951 and 1975. Schizophrenia was assessed by hospital diagnosis through 2010. Cox proportional hazards models were used to investigate future risk for schizophrenia in individuals as a function of their IQ score, and then stratified models using pairs of relatives were used to adjust for familial cluster. Finally, regression models were used to examine the interaction between IQ and genetic liability on risk for schizophrenia.

Results: IQ had a monotonic relationship with schizophrenia risk across the IQ range, with a mean increase in risk of 3.8% per 1-point decrease in IQ; this association was stronger in the lower than the higher IQ range. Co-relative control analyses showed a similar association between IQ and schizophrenia in the general population and in cousin, half-sibling, and full-sibling pairs. A robust interaction was seen between genetic liability to schizophrenia and IQ in predicting schizophrenia risk. Genetic susceptibility for schizophrenia had a much stronger impact on risk of illness for those with low than high intelligence. The IQ-genetic liability interaction arose largely from IQ differences between close relatives.

Conclusions: IQ assessed in late adolescence is a robust risk factor for subsequent onset of schizophrenia. This association is not the result of a declining IQ associated with insidious onset. In this large, representative sample, we found no evidence for a link between genius and schizophrenia. Co-relative control analyses showed that the association between lower IQ and schizophrenia is not the result of shared familial risk factors and may be causal. The strongest effect was seen with IQ differences within families. High intelligence substantially attenuates the impact of genetic liability on the risk for schizophrenia.

Figure 1

Key Features of the Research Design – Data was obtained from 4 major Swedish National Registries: the Conscript Registry, the Population and Multigeneration Registries and the Hospital Discharge Registry. The three major analyses of this paper are illustrated. Examining the risk for schizophrenia as a function of priori IQ is accomplished by matching information from the Conscript Registry, via path 1, to the discharge registry. Performing co-relative analyses of the relationship between IQ and schizophrenia required obtaining male-male co-relative pairs with IQ data from the population, multigeneration and conscript registries and then matching those pairs with the discharge registry. These steps are indicated as path 2. Calculating the genetic risk for schizophrenia, used to jointly predict, along with IQ, the risk for schizophrenia, required the location of available cotwins, parents, siblings and cousins of individuals from the conscript registry in the population and multigeneration registries and then matching them to the discharge registry. These steps are indicated as path 3.

Figure 2

Observed Prevalence of Schizophrenia as a Function of Premorbid IQ score. Schizophrenia is assessed using hospital diagnoses. Only onsets after IQ testing are included.

Figure 3

Hazard Ratios with 95% confidence intervals for schizophrenia as a function of the premorbid IQ score in the general population and in first cousins, half-siblings and full siblings discordant for IQ score. Within these relative pairs with differing IQs, the association between IQ and schizophrenia is as strong as that seen in the general population.

Figure 4

Predicted probability of schizophrenia as a function of premorbid IQ score and five increasing levels of genetic liability to schizophrenia as predicted by risk of illness in parents, full and half-siblings and cousins. These levels correspond to the following familial configurations: i) no relatives affected with schizophrenia; ii) an affected mother; iii) all full siblings affected; iv) an affected monozygotic cotwin and v) an affected father, all full siblings affected and 20% of first cousins affected.