June 4, 2014
Autism Speaks fellow studied children of older mothers; found evidence of environmental influences that may affect brain development.
|Autism Speaks Weatherstone Fellow Esther Berko takes a sample|
of cheek cells from a study participant. (The EEG cap is for
a separate study.) Photo by Ariel Bleicher.
New research may help explain why autism is more common among the children of older mothers. The study, in PLOS-Genetics, implicates an accumulation of changes in the mechanisms that control gene activity in the developing brain.
The lead researcher, Esther Berko of New York’s Einstein School of Medicine, pursued her research with the support of an Autism Speaks Weatherstone Predoctoral Fellowship. She did so in collaboration with John Greally, a pioneer in the field of epigenetics. Epigenetics refers to the mechanisms that control gene activity and how these mechanisms can be changed by environmental influences.
The role of epigenetics in autism is of great interest because, in most cases, genetic mutations alone only partially explain why an individual develops autism spectrum disorder (ASD). By “environmental influences,” researchers mean a broad range of factors including parental age, conditions in the womb and birth complications. These factors are of particular interest because some may be avoidable and greater understanding of their effects may lead to future treatments.
Parental Age and Autism
A large body of research has shown that autism is more common among children of older parents. But why?
With older fathers, studies have associated the increased risk to an age-related build-up of gene mutations in sperm-producing cells. But relatively little research has looked at the factors at play with older moms. Unlike men, who continue to produce sperm through life, women are born with a lifetime of egg cells.
|Dr. Berko and her colleagues performed genetic and epigenetic analyses|
on the sample cheek cells. Photo courtesy Albert Einstein School of Medicine.
The new study involved 47 children with autism and 48 typically developing children – all born to mothers age 35 or older. Unlike most previous autism studies, the participants included a significant number of minority children (Hispanic and African-American).
An Easily Obtained Stand-in for Brain Cells
Of particular interest to researchers, Dr. Berko examined an easily obtained “stand-in” for each child’s brain cells: a swab of cells from the inner cheek. These cells arise from the same stem cells that also form the brain during the earliest stages of embryonic development.
“This would mean that whatever abnormalities we found in the cheek cells of children with an ASD versus typically developed children should exist in their brain cells as well,” Dr. Greally says.
Genetic Versus Epigenetic Changes
Dr. Berko and her colleagues looked for genetic as well as epigenetic changes that might account for increased risk of autism in the children of older moms.
Since the eggs of older mothers are prone to having abnormal numbers of chromosomes, the researchers first analyzed the cells for chromosomal defects that might account for ASD. They found no such problems.
The researchers next examined the children’s cells for evidence of environmental influences on the epigenetic control of embryonic development. Berko and her colleagues carried out several types of genome-wide analyses looking for epigenomic differences that would suggest environmental influences at work.
In the cells from the children with autism, they detected epigenetic changes affecting two groups of genes. Both groups of genes are known to affect brain development and brain cell function and have been previously implicated in autism.
“Our findings suggest that, at least in some individuals with an ASD, the same pathways in the brain seem to hit by both mutations and epigenetic changes,” Dr. Greally says. “So the severity of someone’s ASD may depend on whether or not a gene mutation is accompanied by epigenetic alterations to related genes.”
Are environmental influences responsible for the epigenetic changes?
“We were able to eliminate some other possible causes of ASD such as chromosomal abnormalities, so our findings are consistent with that notion,” Dr. Greally says. “In the case of older mothers at risk for having children with ASD, one possible environmental influence might be the aging process itself, which could disturb epigenetic patterns in their eggs. But there are other possibilities as well. Although much more work is needed, our study reveals a plausible way that environmental influences—which we know are important in ASD—might be exerting their effects.”
Guidance for Future Research
“The role of advanced maternal and paternal age as risk factors for ASD has been replicated several times,” comments Alycia Halladay, Autism Speaks senior director for environmental and clinical sciences. “This study takes previous epidemiology studies a step further to understand the biological mechanisms and potential gene-environment interactions in risk factors for ASD. We need more research in this area, especially the role of epigenetics in the causes of ASD.”
In addition to funding from Autism Speaks, the research received support from the Jonas Ehrlich Charitable Foundation. The investigators also thank Autism Speaks for its help in recruiting study participants.