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Early and Delayed Motherhood Linked to Schizophrenia Risk

Credit: Monkey Business

Credit: Monkey Business

By Sang Hong Lee

A mother’s age when she gives birth is associated with her child’s likelihood of developing schizophrenia, but is this because psychosocial factors associated with the mother's age affect her child's risk, or because women with a higher genetic risk for schizophrenia are more likely to have their first child at an early or late age?

It’s well-known that the age of a child’s parents is a risk factor for a range of mental health issues in children, including common psychiatric disorders like schizophrenia. The age of the father has received the most attention, with risk to children widely assumed to be explained by mutations that occur more frequently in older fathers’ DNA, although other studies question this belief.

There is also new evidence that children of both younger and older mothers may develop psychosis more regularly. A 2014 investigation published in JAMA Psychiatry (http://tinyurl.com/zoukjfv) performed a comprehensive analysis using family data extracted from the Danish Psychiatric Central Register, and reported a higher risk of schizophrenia in children of younger and older mothers compared with those of intermediate age (25–29 years). When the study accounted for the age of the father it found that the likelihood of schizophrenia in children was strongest in mothers younger than 25.

However, these epidemiological observations cannot dissect cause from consequence. It’s unclear if the risk of schizophrenia in children is because of psychological, lifestyle or ageing factors associated with a mother’s age or if women at higher risk for schizophrenia generally have their first child at an earlier or later age.

Our study, published in May in JAMA Psychiatry (http://tinyurl.com/jl4clfh), has tackled this question using gene variants associated with schizophrenia to create a risk profile score for each woman in the general population for whom there was a record of her age at first birth. We tested if there was a relationship between a woman’s age at first birth and her schizophrenia risk profile score using a novel design analysing genomic data from 18,957 cases of schizophrenia and 22,673 controls, and an independent community sample of 12,247 genotyped women documented for age at first birth from Estonia, The Netherlands, Sweden and the United Kingdom.

We found evidence for a connection between genetic factors associated with schizophrenia and genetic factors associated with age at first birth. The U-shaped relationship we observed was consistent with previous reports of a relationship between schizophrenia risk in offspring and maternal age when not adjusted for age of the father.

Our analysis explored the relationship between the genetic risk for schizophrenia and maternal age at first birth in a way that is independent of non-genetic confounding effects. From this it appears that the risk of schizophrenia in children of older mothers is not solely attributable to factors associated with advanced paternal age.

What we found in this study is important because the risk of schizophrenia in children associated with older mothers was generally thought to be caused by the age of the father and genetic mutations that take place in older men. This explanation may now need to be revisited.

Although our study has demonstrated that the genetic risk for schizophrenia can be separated from psychological, social, lifestyle and biological ageing factors in assessing the relationship between schizophrenia and age at first birth, we cannot perfectly explain how genetic and non-genetic factors play a part. Several unknown factors could also influence the genetics involved in schizophrenia and a mother’s age at first birth.

The age of mothers also involves other factors like genetic abnormalities as well as psychological and social characteristics like income and education, both of which are potentially associated with schizophrenia. Relatives of individuals affected with schizophrenia tend to have poor social interactions, which may increase the time it takes to find a mate and therefore delay giving birth, making a mother older. Schizophrenia may also cause a person to take unnecessary risks and behave impulsively, both of which are linked to early pregnancies and childbirth in women. Consequently, the risk of schizophrenia in children because of how old their mothers are may be influenced by shared genetic factors between mothers and offspring.

Other explanations need to be investigated, like the risks for a woman of low IQ or little education, both of which are linked to schizophrenia and early pregnancy. That being said, future research that includes social science measures and information on non-genetic factors will provide a greater understanding of the connection between schizophrenia and a mother’s age when she first gives birth.

We have only considered genetic risk for schizophrenia because sample size, and hence the power to estimate risk allele effect sizes, is greatest. For example, 108 independent risk loci for schizophrenia have been identified compared with only three for bipolar disorder. As genome-wide association study sample sizes for other psychiatric disorders increase, replication of our analyses of these disorders will be possible.


Sang Hong Lee, School of Environmental and Rural Science, University of New England, Armidale.