Paternal age effect: Replication in schizophrenia with intriguing dissociation between bipolar with and without psychosis

Abstract

Advanced paternal age (APA) is a risk factor for schizophrenia (Sz) and bipolar disorder (BP). Putative mechanisms include heritable genetic factors, de novo mutations, and epigenetic mechanisms. Few studies have explored phenotypic features associated with APA. The Genomic Psychiatry Cohort established a clinically characterized repository of genomic samples from subjects with a Sz-BP diagnosis or unaffected controls, 12,975 with parental age information. We estimated relative risk ratios for Sz, schizoaffective depressed and bipolar types (SA-D, SA-B), and BP with and without history of psychotic features (PF) relative to the control group, comparing each paternal age group to the reference group 20-24 years. All tests were two-sided with adjustment for multiple comparisons. Subjects with fathers age 45þ had significantly higher risk for all diagnoses except for BP w/o PF. APA also bore no significant relation to family psychiatric history. In conclusion, we replicated APA as a risk factor for Sz. To our knowledge, this is the first published report of APA in a BP sample stratified by psychosis history, extending this association only in BP w/PF. This suggests that phenotypic expression of the APA effect in Sz-BP spectrum is psychosis, per se, rather than other aspects of these complex disorders. The lack of a significant relationship between paternal age and familial disease patterns suggests that underlying mechanisms of the paternal age effect may involve a complex interaction of heritable and non-heritable factors. The authors discuss implications and testable hypotheses, starting with a focus on genetic mechanisms and endophenotypic expressions of dopaminergic function. Ó 2015 Wiley Periodicals, Inc.

Paternal age and psychiatric disorders: A review

“…Based on current findings, genetic predisposition for SCZ does not seem to account for the relationship between paternal age at childbearing and SCZ occurrence in offspring [Tsuchiya et al, ; Frans et al, ; McGrath et al, ]. Furthermore, the results of Lehrer et al [] are contrary to the assumption that parents with a psychiatric family history tend to postpone parenthood. However, it is still possible that parents with such a genetic vulnerability do not have a family history of SCZ, but rather carry genetic predisposing traits that contribute to a late childbearing pattern.…”

“…For ADHD, BPD, OCD, and MDD fewer studies were reviewed; the number of studies was three (ADHD), six (BPD), one (OCD), and one (MDD). One study of BPD distinguished between BPD with and without psychoses [Lehrer et al, ]. Additionally, several studies considered multiple indices of morbidity [Buizer‐Voskamp et al, ; Wu et al, ; McGrath et al, ; Lehrer et al, ].…”

“…Interestingly, the significantly greater risk in the 20–24‐year age category was rendered insignificant by the adjustment for family history of psychiatric disorders. Lehrer et al [] did not find any significant relationship when calculating the odds of “no psychiatric family history” in each paternal age group.…”

“…The results, which included a correction for co‐variates, are displayed in the upper part of Supplementary Table SVI. Lehrer et al [] found a significantly decreased risk of BPD without psychosis for offspring born to fathers younger than 20 years of age. Two analyses found no association between advanced paternal age and BPD risk, one analysis found a U‐shaped relationship, one analysis showed a monotonic increase in BPD risk with advancing categories of paternal age, and two analyses showed an elevated risk associated only with the oldest age category.…”

“…Studies of BPD, ADHD, and MDD subtypes are scarce. Lehrer et al [] distinguished between SCZ, BPD with and BPD without psychosis, and found different associated risks. This suggests that the paternal age effect was mainly present in offspring with psychotic symptoms, but was absent in BPD without psychotic symptoms.…”