TY - JOUR

T1 - Evidence for Genetic Overlap Between Schizophrenia and Age at First Birth in Women

AU - Mehta, Divya

AU - Tropf, Felix C

AU - Gratten, Jacob

AU - Bakshi, Andrew

AU - Zhu, Zhihong

AU - Bacanu, Silviu-Alin

AU - Hemani, Gibran

AU - Magnusson, Patrik K E

AU - Barban, Nicola

AU - Esko, Tõnu

AU - Metspalu, Andres

AU - Snieder, Harold

AU - Mowry, Bryan J

AU - Kendler, Kenneth S

AU - Yang, Jian

AU - Visscher, Peter M

AU - McGrath, John

AU - Mills, Melinda C

AU - Wray, Naomi R

AU - Lee, S Hong

AU - Andreassen, Ole A.

AU - Bramon, Elvira

AU - Bruggeman, Richard

AU - Buxbaum, Joseph D

AU - Cairns, Murray J

AU - Cantor, Rita M

AU - Cloninger, C Robert

AU - Cohen, David

AU - Crespo-Facorro, Benedicto

AU - Darvasi, Ariel

AU - Delisi, Lynn E

AU - Dinan, Timothy

AU - Djurovic, Srdjan

AU - Donohoe, Gary

AU - Drapeau, Elodie

AU - Escott-Price, Valentina

AU - Freimer, Nelson B

AU - Georgieva, Lyudmila

AU - de Haan, Lieuwe

AU - Henskens, Frans A

AU - Joa, Inge

AU - Julià, Antonio

AU - Khrunin, Andrey

AU - Lerer, Bernard

AU - Limborska, Svetlana

AU - Loughland, Carmel M

AU - Macek, Milan

AU - Magnusson, Patrik K E

AU - Marsal, Sara

AU - Schizophrenia Working Group of the Psychiatric Genomics Consortium

AU - LifeLines Cohort Study

AU - TwinsUK

AU - Werge, Thomas

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

KW - Adult

KW - Alleles

KW - Birth Order

KW - Cohort Studies

KW - Denmark

KW - Female

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Humans

KW - Maternal Age

KW - Phenotype

KW - Pregnancy

KW - Risk

KW - Schizophrenia

KW - Journal Article

U2 - 10.1001/jamapsychiatry.2016.0129

DO - 10.1001/jamapsychiatry.2016.0129

M3 - Journal article

C2 - 27007234

VL - 73

SP - 497

EP - 505

JO - JAMA Psychiatry

JF - JAMA Psychiatry

SN - 2168-622X

IS - 5

ER -