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

https://arctichealth.org/en/permalink/ahliterature282521
Source
JAMA Psychiatry. 2016 May 01;73(5):497-505
Publication Type
Article
Date
May-01-2016
Author
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
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
Source
JAMA Psychiatry. 2016 May 01;73(5):497-505
Date
May-01-2016
Language
English
Publication Type
Article
Keywords
Adult
Alleles
Birth Order
Cohort Studies
Denmark
Female
Genetic Predisposition to Disease - genetics
Genome-Wide Association Study
Humans
Maternal Age
Phenotype
Pregnancy
Risk
Schizophrenia - genetics
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.
PubMed ID
27007234 View in PubMed
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