title: Evidence for Genetic Overlap Between Schizophrenia and Age at First Birth in Women.
abstract: A recently published study of national data by McGrath et al in 2014 showed increased risk of schizophrenia (SCZ) in offspring associated with both early and delayed parental age, consistent with a U-shaped relationship. However, it remains unclear if the risk to the child is due to psychosocial factors associated with parental age or if those at higher risk for SCZ tend to have children at an earlier or later age.
  
  
  
  To determine if there is a genetic association between SCZ and age at first birth (AFB) using genetically informative but independently ascertained data sets.
  
  
  
  This investigation used multiple independent genome-wide association study data sets. The SCZ sample comprised 18 957 SCZ cases and 22 673 controls in a genome-wide association study from the second phase of the Psychiatric Genomics Consortium, and the AFB sample comprised 12 247 genotyped women measured for AFB from the following 4 community cohorts: Estonia (Estonian Genome Center Biobank, University of Tartu), the Netherlands (LifeLines Cohort Study), Sweden (Swedish Twin Registry), and the United Kingdom (TwinsUK). Schizophrenia genetic risk for each woman in the AFB community sample was estimated using genetic effects inferred from the SCZ genome-wide association study.
  
  
  
  We tested if SCZ genetic risk was a significant predictor of response variables based on published polynomial functions that described the relationship between maternal age and SCZ risk in offspring in Denmark. We substituted AFB for maternal age in these functions, one of which was corrected for the age of the father, and found that the fit was superior for the model without adjustment for the father's age.
  
  
  
  We observed a U-shaped relationship between SCZ risk and AFB in the community cohorts, consistent with the previously reported relationship between SCZ risk in offspring and maternal age when not adjusted for the age of the father. We confirmed that SCZ risk profile scores significantly predicted the response variables (coefficient of determination R2 = 1.1E-03, P = 4.1E-04), reflecting the published relationship between maternal age and SCZ risk in offspring by McGrath et al in 2014.
  
  
  
  This study provides evidence for a significant overlap between genetic factors associated with risk of SCZ and genetic factors associated with AFB. It has been reported that SCZ risk associated with increased maternal age is explained by the age of the father and that de novo mutations that occur more frequently in the germline of older men are the underlying causal mechanism. This explanation may need to be revised if, as suggested herein and if replicated in future studies, there is also increased genetic risk of SCZ in older mothers.
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, Australia.
authors.forename: Divya
authors.initials: D
authors.lastname: Mehta
authors.affiliation: Department of Sociology, Interuniversity Center for Social Science Theory and Methodology, University of Groningen, Groningen, the Netherlands3Department of Sociology, Nuffield College, University of Oxford, Oxford, England.
authors.forename: Felix C
authors.initials: FC
authors.lastname: Tropf
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, Australia.
authors.forename: Jacob
authors.initials: J
authors.lastname: Gratten
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Bakshi
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, Australia.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Virginia Institute of Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond5Department of Psychiatry, Virginia Commonwealth University, Richmond.
authors.forename: Silviu-Alin
authors.initials: SA
authors.lastname: Bacanu
authors.affiliation: Medical Research Council Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, England.
authors.forename: Gibran
authors.initials: G
authors.lastname: Hemani
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Patrik K E
authors.initials: PK
authors.lastname: Magnusson
authors.affiliation: Department of Sociology, Nuffield College, University of Oxford, Oxford, England.
authors.forename: Nicola
authors.initials: N
authors.lastname: Barban
authors.affiliation: Estonian Genome Center, University of Tartu, Tartu, Estonia.
authors.forename: Tõnu
authors.initials: T
authors.lastname: Esko
authors.affiliation: Estonian Genome Center, University of Tartu, Tartu, Estonia.
authors.forename: Andres
authors.initials: A
authors.lastname: Metspalu
authors.affiliation: Department of Epidemiology, University of Groningen, The University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Harold
authors.initials: H
authors.lastname: Snieder
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, Australia10Queensland Centre for Mental Health Research, Wacol, Australia.
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Mowry
authors.affiliation: Virginia Institute of Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond5Department of Psychiatry, Virginia Commonwealth University, Richmond11Department of Human and Molecular Genetics, Virginia Commonwealth University, Richm.
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Kendler
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, Australia.
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, Australia.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Visscher
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, Australia.
authors.forename: John J
authors.initials: JJ
authors.lastname: McGrath
authors.affiliation: Department of Sociology, Nuffield College, University of Oxford, Oxford, England.
authors.forename: Melinda C
authors.initials: MC
authors.lastname: Mills
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, Australia.
authors.forename: Naomi R
authors.initials: NR
authors.lastname: Wray
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, Australia12School of Environmental and Rural Science, University of New England, Armidale, Australia.
authors.forename: S Hong
authors.initials: SH
authors.lastname: Lee
authors.affiliation: NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway14Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
authors.forename: Ole A
authors.initials: OA
authors.lastname: Andreassen
authors.affiliation: University College London, London, England.
authors.forename: Elvira
authors.initials: E
authors.lastname: Bramon
authors.affiliation: University Medical Center Groningen, Department of Psychiatry, University of Groningen, Groningen, the Netherlands.
authors.forename: Richard
authors.initials: R
authors.lastname: Bruggeman
authors.affiliation: Department of Human Genetics, Icahn School of Medicine at Mount Sinai, New York, New York18Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York19Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Buxbaum
authors.affiliation: Schizophrenia Research Institute, Sydney, Australia22Priority Centre for Translational Neuroscience and Mental Health, University of Newcastle, Newcastle, Australia23School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, Australia.
authors.forename: Murray J
authors.initials: MJ
authors.lastname: Cairns
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles.
authors.forename: Rita M
authors.initials: RM
authors.lastname: Cantor
authors.affiliation: Department of Psychiatry, Washington University in St Louis, St Louis, Missouri.
authors.forename: C Robert
authors.initials: CR
authors.lastname: Cloninger
authors.affiliation: Department of Child and Adolescent Psychiatry, Assistance Publique Hôpitaux de Paris, Pierre and Marie Curie University, and Institute for Intelligent Systems and Robotics, Paris, France.
authors.forename: David
authors.initials: D
authors.lastname: Cohen
authors.affiliation: CIBERSAM, University Hospital Marqués de Valdecilla, University of Cantabria-IDIVAL, Department of Psychiatry, Santander, Spain28 Centro Investigación Biomédica en Red Salud Mental, Madrid, Spain.
authors.forename: Benedicto
authors.initials: B
authors.lastname: Crespo-Facorro
authors.affiliation: Department of Genetics, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Ariel
authors.initials: A
authors.lastname: Darvasi
authors.affiliation: Schizophrenia Research Institute, Sydney, Australia30VA Boston Health Care System, Brockton, Massachusetts.
authors.forename: Lynn E
authors.initials: LE
authors.lastname: DeLisi
authors.affiliation: Department of Psychiatry, University College Cork, Cork, Ireland.
authors.forename: Timothy
authors.initials: T
authors.lastname: Dinan
authors.affiliation: NORMENT, KG Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen, Bergen, Norway33Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
authors.forename: Srdjan
authors.initials: S
authors.lastname: Djurovic
authors.affiliation: Cognitive Genetics and Therapy Group, School of Psychology and Discipline of Biochemistry, National University of Ireland Galway, Galway, Ireland35Neuropsychiatric Genetics Research Group, Department of Psychiatry, Trinity College Dublin, Dublin, Ireland.
authors.forename: Gary
authors.initials: G
authors.lastname: Donohoe
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Elodie
authors.initials: E
authors.lastname: Drapeau
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, Wales.
authors.forename: Valentina
authors.initials: V
authors.lastname: Escott-Price
authors.affiliation: Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles.
authors.forename: Nelson B
authors.initials: NB
authors.lastname: Freimer
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, Wales.
authors.forename: Lyudmila
authors.initials: L
authors.lastname: Georgieva
authors.affiliation: Department of Psychiatry, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Lieuwe
authors.initials: L
authors.lastname: de Haan
authors.affiliation: Schizophrenia Research Institute, Sydney, Australia39School of Electrical Engineering and Computer Science, University of Newcastle, Newcastle, Australia40Priority Research Centre for Health Behaviour, University of Newcastle, Newcastle, Australia.
authors.forename: Frans A
authors.initials: FA
authors.lastname: Henskens
authors.affiliation: Regional Centre for Clinical Research in Psychosis, Department of Psychiatry, Stavanger University Hospital, Stavanger, Norway.
authors.forename: Inge
authors.initials: I
authors.lastname: Joa
authors.affiliation: Rheumatology Research Group, Vall d'Hebron Research Institute, Barcelona, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Julià
authors.affiliation: Institute of Molecular Genetics, Russian Academy of Sciences, Moscow, Russia.
authors.forename: Andrey
authors.initials: A
authors.lastname: Khrunin
authors.affiliation: Department of Psychiatry, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Bernard
authors.initials: B
authors.lastname: Lerer
authors.affiliation: Institute of Molecular Genetics, Russian Academy of Sciences, Moscow, Russia.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Limborska
authors.affiliation: Schizophrenia Research Institute, Sydney, Australia22Priority Centre for Translational Neuroscience and Mental Health, University of Newcastle, Newcastle, Australia.
authors.forename: Carmel M
authors.initials: CM
authors.lastname: Loughland
authors.affiliation: Department of Biology and Medical Genetics, Second Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
authors.forename: Milan
authors.initials: M
authors.lastname: Macek
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Patrik K E
authors.initials: PK
authors.lastname: Magnusson
authors.affiliation: Rheumatology Research Group, Vall d'Hebron Research Institute, Barcelona, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Marsal
authors.affiliation: VA Boston Health Care System, Brockton, Massachusetts47Department of Psychiatry, Harvard Medical School, Boston, Massachusetts.
authors.forename: Robert W
authors.initials: RW
authors.lastname: McCarley
authors.affiliation: Division of Psychiatry, University of Edinburgh, Edinburgh, Scotland49Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, Scotland.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: McIntosh
authors.affiliation: Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London, England.
authors.forename: Andrew
authors.initials: A
authors.lastname: McQuillin
authors.affiliation: Department of Medical Genetics, University of Pécs, Pécs, Hungary52Szentagothai Research Center, University of Pécs, Pécs, Hungary.
authors.forename: Bela
authors.initials: B
authors.lastname: Melegh
authors.affiliation: Schizophrenia Research Institute, Sydney, Australia53School of Psychology, University of Newcastle, Newcastle, Australia.
authors.forename: Patricia T
authors.initials: PT
authors.lastname: Michie
authors.affiliation: Cognitive Genetics and Therapy Group, School of Psychology and Discipline of Biochemistry, National University of Ireland Galway, Galway, Ireland35Neuropsychiatric Genetics Research Group, Department of Psychiatry, Trinity College Dublin, Dublin, Ireland.
authors.forename: Derek W
authors.initials: DW
authors.lastname: Morris
authors.affiliation: Department of Psychiatry, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Kieran C
authors.initials: KC
authors.lastname: Murphy
authors.affiliation: Center for Contextual Psychiatry, Department of Neuroscience, KU Leuven, Leuven, Belgium.
authors.forename: Inez
authors.initials: I
authors.lastname: Myin-Germeys
authors.affiliation: Department of Psychiatry, University of Colorado Denver, Aurora.
authors.forename: Ann
authors.initials: A
authors.lastname: Olincy
authors.affiliation: Institute of Psychiatry, King's College London, London, England58Maastricht University Medical Centre, South Limburg Mental Health Research and Teaching Network, EURON, Maastricht, the Netherlands.
authors.forename: Jim
authors.initials: J
authors.lastname: Van Os
authors.affiliation: Schizophrenia Research Institute, Sydney, Australia59Melbourne Neuropsychiatry Centre, Department of Psychiatry, University of Melbourne and Melbourne Health, Melbourne, Australia.
authors.forename: Christos
authors.initials: C
authors.lastname: Pantelis
authors.affiliation: Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, the Netherlands61Department of Complex Trait Genetics, Neuroscience Campus Amsterdam, VU University Medical Center.
authors.forename: Danielle
authors.initials: D
authors.lastname: Posthuma
authors.affiliation: Department of Psychiatry, University of Oxford, Oxford, England.
authors.forename: Digby
authors.initials: D
authors.lastname: Quested
authors.affiliation: Schizophrenia Research Institute, Sydney, Australia22Priority Centre for Translational Neuroscience and Mental Health, University of Newcastle, Newcastle, Australia.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schall
authors.affiliation: Schizophrenia Research Institute, Sydney, Australia23School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, Australia64Hunter New England Health Service, Newcastle, Australia.
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Scott
authors.affiliation: Department of Psychiatry, Harvard Medical School, Boston, Massachusetts65Massachusetts Mental Health Center Public Psychiatry Division, Beth Israel Deaconess Medical Center, Boston.
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Seidman
authors.affiliation: Department of Medical Genetics, Medical University, Sofia, Bulgaria.
authors.forename: Draga
authors.initials: D
authors.lastname: Toncheva
authors.affiliation: Schizophrenia Research Institute, Sydney, Australia23School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, Australia67Priority Research Centre for Translational Neuroscience and Mental Health, University of Newcastle, Newcastle.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Tooney
authors.affiliation: Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: John
authors.initials: J
authors.lastname: Waddington
authors.affiliation: Lieber Institute for Brain Development, Baltimore, Maryland70Department of Psychiatry and Behavioral Sciences, The Johns Hopkins School of Medicine, Baltimore, Maryland71Department of Neurology, The Johns Hopkins School of Medicine, Baltimore, Maryland72.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Weinberger
authors.affiliation: Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: Mark
authors.initials: M
authors.lastname: Weiser
authors.affiliation: Schizophrenia Research Institute, Sydney, Australia23School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, Australia.
authors.forename: Jing Qin
authors.initials: JQ
authors.lastname: Wu
mesh_terms: D000328:Adult; D000483:Alleles; D001722:Birth Order; D015331:Cohort Studies; D003718:Denmark; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D008423:Maternal Age; D010641:Phenotype; D011247:Pregnancy; D012306:Risk; D012559:Schizophrenia / Q000235:genetics*