Parental Age and Risk of Schizophrenia: A Case-control Study
Byrne M, Agerbo E, Ewald H, Eaton WW and Mortensen PB;
Commented by , 29 Jul 2003
Aim of the study
It has been suggested that advanced paternal age might be a risk factor for schizophrenia. De novo mutations are associated with higher age and it has been estimated that such de novo mutations are approximately two times higher in the male than in the female germline. The aim of the study were:
1. to replicate the results of a previous report that found a clear association between paternal age and risk for schizophrenia in a sample collected from a national register
2. to examine whether the association between parental age and risk of schizophrenia could be explained by known risk factors for the disorder such as season of birth, place of birth, sibship characteristics and psychiatric history while possible confounding socioeconomic factors such as education, marital status and parental wealth were controlled for.
Methods
The authors used the data from a Danish national register for a case-control study. 7704 patients with an ICD-8 or ICD-10 diagnosis of schizophrenia who were admitted to Danish psychiatric facilities between 1981 and 1998 were used for the analysis and compared to 192 590 population controls who were matched for time, age and sex, their parents and siblings.
Logistic regression was used to examine the association between the risk for schizophrenia and parental age while family socioeconomic and demographic factors and family psychiatric history were controlled for.
Results
The authors found an association between advanced paternal and maternal age and increased risk for schizophrenia in univariate analyses. An increased risk for schizophrenia was found in patients whose fathers were 50 years or older despite controlling for socioeconomic factors and family psychiatric history.
When sex-specific analyses were carried out the risk of schizophrenia was increased for male patients whose fathers were 55 years or older. The incidence rate ratio [IRR] was 2.10; 95% confidence interval [CI], 1.35-3.28. For women there was an even more prominent association between the risk of schizophrenia and paternal age. For fathers aged between 50 and 54 years the IRR was 2.22 (95% CI, 1.44-3.44) and for fathers 55 years or older the IRR was 3.53 (95% CI, 1.82-6.83). Less pronounced associations between maternal age and risk for schizophrenia were found, as well.
Discussion
Several theories have been presented to explain the association between increased paternal age and schizophrenia. One is the psychological distress that is caused by losing a father relatively early due to his high age.
However, the death of a parent or other family member was not associated with an increased risk for schizophrenia in the authors’ final model. Another explanation might be factors why some of the parents of people with schizophrenia marry relatively late.
However, a strength of the study is that the authors could rule out the effect of family history of schizophrenia or other major psychiatric disorders. Thus, the increased risk was not restricted to those with other family members suffering from the disorder. The authors emphasize that the increased risk of schizophrenia was especially pronounced in females. They argue that the most likely explanation for the effect of parental age are spontaneous de novo mutations, because these are more frequent in older subjects.
The more pronounced risk in females suggests that these de novo mutations might in part happen on X-chromosomes, because these are always passed from fathers to daughters.