Advanced Paternal Age Increases Risk of Schizophrenia in Offspring

father and son

ANeuropsychiatric disorders are complex genetic diseases, usually of unknown pathogenesis. Although schizophrenia is under strong negative genetic selection, its genetic risk alleles have not been gradually eliminated from the population. For decades, numerous studies have shown an association between advanced paternal age (APA) and increased risk for schizophrenia.

It has been reported that schizophrenic patients without family history are more likely to have older fathers than those with family history. Consequentially, advanced paternal age is argued to be a crucial risk factor for schizophrenia. It increases the risk of early-onset schizophrenia in offspring.

There is extensive evidence showing association between advanced paternal age at conception and a series of negative outcomes in offspring. These adverse effects include Mendelian (single-gene) disorders, those with a more complex etiology (autism, schizophrenia), with birth complications and nonclinical phenotypes (for example, IQ and academic achievement).

The first neuropsychiatric condition associated with advanced paternal age is schizophrenia. There have been multiple epidemiological studies which suggest that there exists a relationship between advanced paternal age at conception and adverse neurodevelopmental outcomes in offspring and a higher risk factor for schizophrenia. There is, however, lacking, conclusive evidence on how age-related changes in paternal gametes, or age-independent behavioral traits affect neural development. Some researchers have suggested that the origins the effects of advanced paternal age are probably multidimensional and involves both inherited predisposition and de novo events.

The risk for this disorder was shown to be elevated already for offspring of fathers in their mid-to-late 30s, and to continue to increase together with paternal age.

The likelihood increased by two to three times for children of fathers in their 40s at conception.

There has been association between advanced paternal age and both autism and schizophrenia. This is quite interesting because of the phenotypic and genetic overlap between them. They are both neurological conditions and characterized by social impairment, delay in development of several cognitive and perceptual abilities.  

John Krystal, MD, Editor of Biological Psychiatry said “presumably, advanced paternal age increases risk for early-onset schizophrenia because advancing age is associated with an accumulation of mutations. These age-related mutations appear to be distinct from those more commonly associated with the risk for schizophrenia. It would be important to understand the distinct neural mechanisms through which advanced paternal age influenced the age of onset”.

Identifying these mechanisms is of particular concern with the increasing age of fathers. The findings that the association with risk of early-onset schizophrenia exists after accounting for paternal and maternal polygenic risk provides an important advance in understanding the advanced paternal age effect on schizophrenia.

Some researchers postulate that inherited and de novo factors present complementary influences contributing to the epidemiological observations. Other factors that are also likely implicated include selection mechanisms, epigenetic alterations and accumulation of other lifetime exposures.

Considering solely the risk for neuropsychiatric disorders, current evidence does not suggest that men should be discouraged from having a child at an older age. Given the low prevalence of these disorders at baseline, even a fivefold increase in the odds ratio under an assumption of strong de novo effects, would yield a low probability that the conceived child will have autism or schizophrenia as a result of higher paternal age. Nevertheless, more evidence is still needed to provide men and their partners with informed, reliable and accurate advice regarding the risks of delayed fatherhood.