title: 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 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. © 2015 Wiley Periodicals, Inc.
authors.affiliation: Department of Psychiatry, Wright State University, Dayton, Ohio.|Summit Behavioral Healthcare, Ohio Department of Mental Health & Addiction Services, Cincinnati, Ohio.
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Lehrer
authors.affiliation: College of Medicine, State University of New York Downstate Medical Center, Brooklyn, New York.|Department of Psychiatry and the Behavioral Sciences, University of Southern California, Los Angeles, California.
authors.forename: Michele T
authors.initials: MT
authors.lastname: Pato
authors.affiliation: Department of Psychiatry, Wright State University, Dayton, Ohio.|Department of Community Health, Wright State University, Dayton, Ohio.
authors.forename: Ramzi W
authors.initials: RW
authors.lastname: Nahhas
authors.affiliation: Department of Psychiatry, Georgia Medical College at Georgia Regents University, Augusta, Georgia.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Miller
authors.affiliation: Department of Psychiatry, New York University, New York, New York.
authors.forename: Dolores
authors.initials: D
authors.lastname: Malaspina
authors.affiliation: Department of Psychiatry, Georgia Medical College at Georgia Regents University, Augusta, Georgia.|Office of the Dean, Georgia Medical College at Georgia Regents University, Augusta, Georgia.
authors.forename: Peter F
authors.initials: PF
authors.lastname: Buckley
authors.affiliation: Department of Psychiatry and the Behavioral Sciences, University of Southern California, Los Angeles, California.
authors.forename: Janet L
authors.initials: JL
authors.lastname: Sobell
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Julie
authors.initials: J
authors.lastname: Walsh-Messinger
authors.lastname: Genomic Psychiatry Cohort Consortium
authors.affiliation: College of Medicine, State University of New York Downstate Medical Center, Brooklyn, New York.|Department of Psychiatry and the Behavioral Sciences, University of Southern California, Los Angeles, California.
authors.forename: Carlos N
authors.initials: CN
authors.lastname: Pato
mesh_terms: D000328:Adult; D000367:Age Factors; D001714:Bipolar Disorder / Q000235:genetics* / Q000378:metabolism / Q000523:psychology; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D010331:Paternal Age; D000072740:Paternal Inheritance / Q000235:genetics*; D011618:Psychotic Disorders / Q000235:genetics* / Q000378:metabolism / Q000523:psychology; D012307:Risk Factors; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism; D012565:Schizophrenic Psychology; D055815:Young Adult
keywords: bipolar; paternal age; phenotype; psychosis; schizophrenia