Evidence for Genetic Overlap Between Schizophrenia and Age at First Birth in Women

Divya Mehta, Felix C. Tropf, Jacob Gratten, Andrew Bakshi, Zhihong Zhu, Silviu-Alin Bacanu, Gibran Hemani, Patrik K. E. Magnusson, Nicola Barban, Tõnu Esko, Andres Metspalu, Harold Snieder, Bryan J. Mowry, Kenneth S. Kendler, Jian Yang, Peter M. Visscher, John J. McGrath, Melinda C. Mills, Naomi R. Wray, S. Hong Lee, Ole A. Andreassen, Elvira Bramon, Richard Bruggeman, Joseph D. Buxbaum, Murray J. Cairns, Rita M. Cantor, C. Robert Cloninger, David Cohen, Benedicto Crespo-Facorro, Ariel Darvasi, Lynn E. DeLisi, Timothy Dinan, Srdjan Djurovic, Gary Donohoe, Elodie Drapeau, Valentina Escott-Price, Nelson B. Freimer, Lyudmila Georgieva, Lieuwe de Haan, Frans A. Henskens, Inge Joa, Antonio Julià, Andrey Khrunin, Bernard Lerer, Svetlana Limborska, Carmel M. Loughland, Milan Macek, Patrik K. E. Magnusson, Sara Marsal, Robert W. McCarley, Andrew M. McIntosh, Andrew McQuillin, Bela Melegh, Patricia T. Michie, Derek W. Morris, Kieran C. Murphy, Inez Myin-Germeys, Ann Olincy, Jim Van Os, Christos Pantelis, Danielle Posthuma, Digby Quested, Ulrich Schall, Rodney J. Scott, Larry J. Seidman, Draga Toncheva, Paul A. Tooney, John Waddington, Daniel R. Weinberger, Mark Weiser, Jing Qin Wu

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.