Paternal age at time of birth is a robust risk factor for schizophrenia and related neurodevelopmental disorders such as autism spectrum disorder. However, very little is known how advanced age of the father at time of birth may specifically result in increased risk to develop these diseases in the offspring. Several studies have shown that the increased de novo mutation rate in sperm of fathers with advancing age does insufficiently explain the increased risk observed in a number of monogenic diseases. A recent finding that there are widespread RNA and DNA sequence differences in the human transcriptome with individual variation in abundance of these differences has highlighted another possible mechanism playing a role in the molecular basis of disease susceptibility. In this explorative study we hypothesize that increased paternal age leads to increased abundance of RNA-DNA differences in the offspring, which contributes to disease susceptibility of schizophrenia. In hundred sibling pairs consisting of schizophrenia patient and unaffected sibling we will compare RNA and DNA sequence differences using whole blood samples. These subjects are selected for having younger (ages ?25) and older (ages ?40) fathers at time of birth, so that we can establish the effects of paternal age as well as disease status on the abundance of RNA and DNA sequence differences.
Paternal age at time of birth is a robust risk factor for schizophrenia and autism but very little is known how advanced age of the father at time of birth may results in increased risk to develop disease in the offspring. This study explores whether the accuracy of the gene transcription machinery in the offspring is affected by having an older father and contributes to schizophrenia susceptibility.