IMPORTANCE: 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. OBJECTIVE: To determine if there is a genetic association between SCZ and age at first birth (AFB) using genetically informative but independently ascertained data sets. DESIGN, SETTING, AND PARTICIPANTS: 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. MAIN OUTCOMES AND MEASURES: 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. RESULTS: 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. CONCLUSIONS AND RELEVANCE: 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.

Center for Contextual Psychiatry Department of Neuroscience KU Leuven Leuven Belgium

Center for Neurobehavioral Genetics Semel Institute for Neuroscience and Human Behavior University of California Los Angeles

CIBERSAM University Hospital Marqués de Valdecilla University of Cantabria IDIVAL Department of Psychiatry Santander Spain28 Centro Investigación Biomédica en Red Salud Mental Madrid Spain

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

Department of Biology and Medical Genetics 2nd Faculty of Medicine and University Hospital Motol Prague Czech Republic

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

Department of Epidemiology University of Groningen The University Medical Center Groningen Groningen the Netherlands

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

Department of Genetics The Hebrew University of Jerusalem Jerusalem Israel

Department of Human Genetics David Geffen School of Medicine University of California Los Angeles

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

Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden

Department of Medical Genetics Medical University Sofia Bulgaria

Department of Medical Genetics University of Pécs Pécs Hungary52Szentagothai Research Center University of Pécs Pécs Hungary

Department of Psychiatry Academic Medical Centre University of Amsterdam Amsterdam the Netherlands

Department of Psychiatry Hadassah Hebrew University Medical Center Jerusalem Israel

Department of Psychiatry Harvard Medical School Boston Massachusetts65Massachusetts Mental Health Center Public Psychiatry Division Beth Israel Deaconess Medical Center Boston

Department of Psychiatry Icahn School of Medicine at Mount Sinai New York New York

Department of Psychiatry Royal College of Surgeons in Ireland Dublin Ireland

Department of Psychiatry University College Cork Cork Ireland

Department of Psychiatry University of Colorado Denver Aurora

Department of Psychiatry University of Oxford Oxford England

Department of Psychiatry Washington University in St Louis St Louis Missouri

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

Department of Sociology Nuffield College University of Oxford Oxford England

Division of Psychiatry University of Edinburgh Edinburgh Scotland49Centre for Cognitive Ageing and Cognitive Epidemiology University of Edinburgh Edinburgh Scotland

Estonian Genome Center University of Tartu Tartu Estonia

Institute of Molecular Genetics Russian Academy of Sciences Moscow Russia

Institute of Psychiatry King's College London London England58Maastricht University Medical Centre South Limburg Mental Health Research and Teaching Network EURON Maastricht the Netherlands

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

Medical Research Council Integrative Epidemiology Unit School of Social and Community Medicine University of Bristol Bristol England

Molecular and Cellular Therapeutics Royal College of Surgeons in Ireland Dublin Ireland

Molecular Psychiatry Laboratory Division of Psychiatry University College London London England

MRC Centre for Neuropsychiatric Genetics and Genomics Institute of Psychological Medicine and Clinical Neurosciences School of Medicine Cardiff University Cardiff Wales

NORMENT KG Jebsen Centre for Psychosis Research Department of Clinical Science University of Bergen Bergen Norway33Department of Medical Genetics Oslo University Hospital Oslo Norway

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

Queensland Brain Institute The University of Queensland Brisbane Australia

Queensland Brain Institute The University of Queensland Brisbane Australia10Queensland Centre for Mental Health Research Wacol Australia

Queensland Brain Institute The University of Queensland Brisbane Australia12School of Environmental and Rural Science University of New England Armidale Australia

Regional Centre for Clinical Research in Psychosis Department of Psychiatry Stavanger University Hospital Stavanger Norway

Rheumatology Research Group Vall d'Hebron Research Institute Barcelona Spain

Schizophrenia Research Institute Sydney Australia22Priority Centre for Translational Neuroscience and Mental Health University of Newcastle Newcastle Australia

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

Schizophrenia Research Institute Sydney Australia23School of Biomedical Sciences and Pharmacy University of Newcastle Callaghan Australia

Schizophrenia Research Institute Sydney Australia23School of Biomedical Sciences and Pharmacy University of Newcastle Callaghan Australia64Hunter New England Health Service Newcastle Australia

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

Schizophrenia Research Institute Sydney Australia30VA Boston Health Care System Brockton Massachusetts

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

Schizophrenia Research Institute Sydney Australia53School of Psychology University of Newcastle Newcastle Australia

Schizophrenia Research Institute Sydney Australia59Melbourne Neuropsychiatry Centre Department of Psychiatry University of Melbourne and Melbourne Health Melbourne Australia

Sheba Medical Center Tel Hashomer Israel

University College London London England

University Medical Center Groningen Department of Psychiatry University of Groningen Groningen the Netherlands

VA Boston Health Care System Brockton Massachusetts47Department of Psychiatry Harvard Medical School Boston Massachusetts

Virginia Institute of Psychiatric and Behavioral Genetics Virginia Commonwealth University Richmond5Department of Psychiatry Virginia Commonwealth University Richmond

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

See more in PubMed

Bassett AS, Bury A, Hodgkinson KA, Honer WG. Reproductive fitness in familial schizophrenia. Schizophr Res. 1996;21(3):151–160. PubMed PMC

MacCabe JH, Koupil I, Leon DA. Lifetime reproductive output over two generations in patients with psychosis and their unaffected siblings: the Uppsala 1915–1929 Birth Cohort Multigenerational Study. Psychological medicine. 2009;39(10):1667–1676. PubMed

McGrath JJ, Hearle J, Jenner L, Plant K, Drummond A, Barkla JM. The fertility and fecundity of patients with psychoses. Acta psychiatrica Scandinavica. 1999;99(6):441–446. PubMed

D’Onofrio BM, Rickert ME, Frans E, et al. Paternal age at childbearing and offspring psychiatric and academic morbidity. JAMA psychiatry. 2014;71(4):432–438. PubMed PMC

Das M, Al-Hathal N, San-Gabriel M, et al. High prevalence of isolated sperm DNA damage in infertile men with advanced paternal age. Journal of assisted reproduction and genetics. 2013;30(6):843–848. PubMed PMC

Kong A, Frigge ML, Masson G, et al. Rate of de novo mutations and the importance of father’s age to disease risk. Nature. 2012;488(7412):471–475. PubMed PMC

Jaffe AE, Eaton WW, Straub RE, Marenco S, Weinberger DR. Paternal age, de novo mutations and schizophrenia. Mol Psychiatry. 2014;19(3):274–275. PubMed PMC

Petersen L, Mortensen PB, Pedersen CB. Paternal age at birth of first child and risk of schizophrenia. Am J Psychiatry. 2011;168(1):82–88. PubMed

Eaton WW, Mortensen PB, Frydenberg M. Obstetric factors, urbanization and psychosis. Schizophr Res. 2000;43(2–3):117–123. PubMed

Hultman CM, Ohman A, Cnattingius S, Wieselgren IM, Lindstrom LH. Prenatal and neonatal risk factors for schizophrenia. The British journal of psychiatry : the journal of mental science. 1997;170:128–133. PubMed

McGrath JJ, Petersen L, Agerbo E, Mors O, Mortensen PB, Pedersen CB. A comprehensive assessment of parental age and psychiatric disorders. JAMA psychiatry. 2014;71(3):301–309. PubMed

Lee SH, Ripke S, Neale BM, et al. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat Genet. 2013;45(9):984–994. PubMed PMC

Tropf FC, Stulp G, Barban N, et al. Human fertility, molecular genetics, and natural selection in modern societies. PLoS One. 2015;10(6):e0126821. PubMed PMC

Mills M, Tropf F. The biodemography of fertility: A review and future research frontiers. Kölner Zeitschrift für Soziologie und Sozialpsychologie. 2015 PubMed PMC

Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511(7510):421–427. PubMed PMC

Maier R, Moser G, Chen GB, et al. Joint analysis of psychiatric disorders increases accuracy of risk prediction for schizophrenia, bipolar disorder, and major depressive disorder. Am J Hum Genet. 2015;96(2):283–294. PubMed PMC

Purcell SM, Wray NR, Stone JL, et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature. 2009;460(7256):748–752. PubMed PMC

Wray NR, Lee SH, Mehta D, Vinkhuyzen AAE, Dudbridge F, Middeldorp CM. Research Review: Polygenic methods and their application to psychiatric traits. Journal of Child Psychology and Psychiatry. 2014;55(10):1068–1087. PubMed

Leridon H. A new estimate of permanent sterility by age: sterility defined as the inability to conceive. Population studies. 2008;62(1):15–24. PubMed

Lesthaeghe R. The unfolding story of the second demographic transition. Population and development review. 2010;36(2):211–251. PubMed

Fergusson DM, Woodward LJ. Maternal age and educational and psychosocial outcomes in early adulthood. Journal of child psychology and psychiatry, and allied disciplines. 1999;40(3):479–489. PubMed

Moore GS, Kneitel AW, Walker CK, Gilbert WM, Xing G. Autism risk in small- and large-for-gestational-age infants. American journal of obstetrics and gynecology. 2012;206(4):314, e311–319. PubMed PMC

Tu YK, Kellett M, Clerehugh V, Gilthorpe MS. Problems of correlations between explanatory variables in multiple regression analyses in the dental literature. British dental journal. 2005;199(7):457–461. PubMed

Belsley D. A Guide to using the collinearity diagnostics. Computer Science in Economics and Management. 1991;4(1):33–50.

Farrar DE, Glauber RR. Multicollinearity in Regression Analysis: The Problem Revisited. The Review of Economics and Statistics. 49:92–107.

Bellack AS, Morrison RL, Wixted JT, Mueser KT. An analysis of social competence in schizophrenia. The British journal of psychiatry : the journal of mental science. 1990;156:809–818. PubMed

Giordano GN, Ohlsson H, Sundquist K, Sundquist J, Kendler KS. The association between cannabis abuse and subsequent schizophrenia: a Swedish national co-relative control study. Psychological medicine. 2015;45(2):407–414. PubMed PMC

Salas-Wright CP, Vaughn MG, Ugalde J, Todic J. Substance use and teen pregnancy in the United States: evidence from the NSDUH 2002-2012. Addictive behaviors. 2015;45:218–225. PubMed PMC

Reddy LF, Lee J, Davis MC, et al. Impulsivity and risk taking in bipolar disorder and schizophrenia. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2014;39(2):456–463. PubMed PMC

Morra LF, Gold JM, Sullivan SK, Strauss GP. Predictors of neuropsychological effort test performance in schizophrenia. Schizophrenia research. 2015;162(1–3):205–210. PubMed PMC

Sklar P, Ripke S, Scott LJ, et al. Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. Nature Genetics. 2011;43(10):977–983. PubMed PMC