New research has found that some cases of autism spectrum disorder (ASD) may result from environmental influences rather than gene mutations.
Scientists at Albert Einstein College of Medicine of Yeshiva University say their research may help explain why older mothers are at an increased risk for having children with autism.
According to the Center for Disease Control and Prevention, one in 68 U.S. children has an ASD — a 30 percent rise from one in 88 two years ago.
A significant number of people with an ASD have gene mutations, but a number of studies — including those involving identical twins, in which one twin has ASD and the other does not — have shown that not all ASD cases arise from mutations, according to the researchers.
A study of more than 14,000 autistic children published earlier this month in the Journal of the American Medical Association concluded that gene abnormalities could account for only half the risk for developing ASD.
The other half was attributable to “nongenetic influences,” meaning environmental factors, such as conditions in the womb or a pregnant woman’s stress level or diet, researchers explain.
Previous studies have also found that fathers over the age of 40 are more likely to have children with an ASD, probably because of gene mutations that accumulate over the years in sperm-making cells. Yet little is known about older mothers and the connection to ASD, according to the Einstein researchers.
That is why they set out to look for genetic as well as environmental influences that might account for older mothers’ increased risk for having children with ASD.
Their study, led by Esther Berko, an M.D./Ph.D. student in the lab of Dr. John Greally involved 47 children with ASD and 48 typically developing (TD) children of women aged 35 and over.
The researchers note that unlike other ASD studies, theirs included a “significant number” of minority children, including Hispanic and African-American, from the Bronx.
They decided to examine the buccal epithelial cells that line the cheek for evidence of genetic and environmental differences.
“We hypothesized that whatever influences lead to ASD in children of older women probably are already present in the reproductive cells that produce the embryo or during the very earliest stages of embryonic development — in cells that give rise to both the buccal epithelium and the brain,” said Greally, the study’s senior author, a professor of genetics, medicine and pediatrics, director of the Center for Epigenomics, and an attending physician at The Children’s Hospital at Montefiore, N.Y.,
“This would mean that whatever abnormalities we found in the cheek cells of children with an ASD versus TD children should exist in their brain cells as well.”
Small brushes were used to harvest cheek cells from the children living in the Bronx and throughout the U.S., as well as in Chile and Israel.
Since the eggs of older mothers are prone to having abnormal numbers of chromosomes, the researchers noted they first analyzed the cells for abnormal chromosome numbers, as well as other chromosomal defects that might account for ASD. No such problems were found in any of the cells, they reported.
The researchers then examined the children’s cells for evidence of environmental effects.
“If environmental influences were exerted during embryonic development, they would encode a ‘memory’ in cells that we can detect as chemical alterations of genes,” said Greally. “Most of these so-called epigenetic alterations are in the form of methyl groups that chemically bind to DNA. Such methyl groups are vital for controlling gene activity, but changes in methylation patterns can dysregulate cell function by altering gene expression or by silencing genes entirely.”
The researchers carried out several types of genome-wide methylation analyses on the cells, looking for epigenomic differences that would suggest environmental influences at work.
The researchers detected two groups of genes that were epigenetically distinctive in children with ASD compared with TD children. These genes are known to be expressed in the brain and code for proteins involved in nerve transmission functions previously shown to be impaired in ASD, they noted.
In addition, these two gene groups tended to interact with genes already known to be mutated in children with ASD, according to the study’s findings.
“Genes interact with each other to create molecular pathways that carry out important functions,” said Greally. “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. So the severity of someone’s ASD may depend on whether or not a gene mutation is accompanied by epigenetic alterations to related genes.”
So are environmental influences responsible for the epigenetic changes that dysregulate these genes?
“We were able to eliminate some other possible causes of ASD, such as chromosomal abnormalities, so our findings are consistent with that notion,” said Greally.
“In the case of older mothers at risk for having children with ASDs, one possible environmental influence might the aging process itself, which could disturb epigenetic patterns in their eggs, but there are other possibilities as well,” he said.
“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.”
The study was published in PLOS Genetics.