Advanced Paternal Age and Early Onset of Schizophrenia in Sporadic Cases: Not Confounded by Parental Polygenic Risk for Schizophrenia

Background: Whether paternal age effect on schizophrenia is a causation or just an association due to confounding by selection into late parenthood is still debated. We investigated the association between paternal age and early onset of schizophrenia in offspring, controlling for both paternal and maternal predisposition to schizophrenia as empirically estimated using polygenic risk score (PRS) derived from the Psychiatric Genomics Consortium.

Methods: Among 2923 sporadic schizophrenia cases selected from the Schizophrenia Trio Genomic Research in Taiwan project, 1649 had parents' genotyping data. The relationships of paternal schizophrenia PRS to paternal age at first birth (AFB) and of maternal schizophrenia PRS to maternal AFB were examined. A logistic regression model of patients' early onset of schizophrenia (≤18 years old) on paternal age was conducted.

Results: Advanced paternal age over 20 years exhibited a trend of an increasing proportion of early onset of schizophrenia (odds ratio per 10-year increase in paternal age = 1.28, p = .007) after adjusting for maternal age, sex, and age. Older paternal AFB also exhibited an increasing trend of paternal schizophrenia PRS. Additionally, a U-shaped relationship between maternal AFB and maternal schizophrenia PRS was observed. After adjusting for both paternal and maternal schizophrenia PRS, the association of paternal age with patients' early onset of schizophrenia remained (odds ratio = 1.29, p = .04).

Conclusions: The association between paternal age and early onset of schizophrenia was not confounded by parental PRS for schizophrenia, which partially captures parental genetic vulnerability to schizophrenia. Our findings support an independent role of paternal age per se in increased risk of early onset of schizophrenia in offspring.