Genetic analysis of the relationship between parental age and risk of psychiatric disorders (2016–2019)
Advanced paternal age is a well-documented risk factor for psychiatric disorders, including schizophrenia and autism. It is commonly assumed that age-related de novo mutations are the underlying causal mechanism, based on evidence for increasing mutation rate with paternal age and increased risk of psychiatric disorders from de novo mutations. This mechanism must logically account for some of the observed risk, but theoretical genetic models, presented here as pilot data, suggest that de novo mutations explain only 10-50% of the risk, and there is epidemiological evidence (e.g. advanced paternal age is not a risk factor for schizophrenia after correcting for paternal age-at-first child, and children of teenaged parents are also at higher risk) suggesting that alternative hypotheses warrant closer scrutiny. The hypothesis we will test is that delayed, or conversely early parenthood may be a consequence of higher than average liability for mental illness. In simple terms, children are more likely to be affected if their parents carry higher than average genetic liability, because psychiatric disorders are highly heritable. If elevated genetic liability is also associated with delayed fatherhood, or early motherhood, then an indirect association may be observed between parental age and risk of psychiatric illness. The aim of this proposal is to quantify the contribution of inherited genetic variation versus de novo mutations to the relationship between parental age and risk of psychiatric disorders. Understanding the genetic basis of increased risk of psychiatric disorders due to parental age is vitally important if we are to understand the public health implications of the trend towards delayed parenthood in industrialised economies.