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

Douglas S. Lehrer, Michele T. Pato, Ramzi W. Nahhas, Brian R. Miller, Dolores Malaspina, Peter F. Buckley, Janet L. Sobell, Julie Walsh-Messinger, Carlos N. Pato, Abbott, Maria Helena Azevedo, Evelyn J. Bromet, Michael A. Escamilla, Ayman H. Fanous, Laura J. Fochtmann, Becky Kinkead, James A. Knowles, Fabio Macciardi, Antonio Macedo, Stephen R. MarderSteven A. McCarroll, Helena Medeiros, Christopher P. Morley, Humberto Nicolini, J Rakofsky Jeffrey J Rakofsky, Mark H. Rapaport, Diana O. Perkins, Pamela Sklar, Jordan W. Smoller, Marquis Vawter, Genomic Psychiatry Cohort Consortium

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


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 45+ 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.

Original languageEnglish (US)
Pages (from-to)495-505
Number of pages11
JournalAmerican Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
Issue number4
StatePublished - Jun 1 2016
Externally publishedYes


  • Bipolar
  • Paternal age
  • Phenotype
  • Psychosis
  • Schizophrenia

ASJC Scopus subject areas

  • Genetics(clinical)
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience


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