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Genes, ozone, and autism
The study is the first to look at the combined effects of genome-wide genetic change and environmental risk factors for autism, and the first to identify an interaction between genes and environment that leads to an increase in risk for autism. The paper describing the research appears online in the journal Autism Research.
"Autism, like most human diseases, is complex," said Scott B. Selleck PhD, professor of biochemistry and molecular biology at Pennsylvania State Univerity, USA, and one of the leaders of the research team. "There are probably hundreds, if not thousands, of genes involved in autism — and with very few exceptions, they have been studied independent of environmental contribution.
"Our team of researchers represents a merger of people with genetic expertise and environmental epidemiologists. This allows us to answer questions about how genetic and environmental risk factors for autism interact."
The team looked at copy-number variation, or deletions and duplications of repeating elements in our genes that lead to variation among individuals by the sheer number of these repeats. They then looked at five types of air pollution: (1) traffic-related air pollution, (2) nitrogen oxides, (3) two sizes of particulate matter, and (4) ozone — in a large group of individuals with autism cpmpared with a well-matched set of typically developing people without autism — as the control group.
Study participants with autism were recruited from the Childhood Autism Risks from Genetics and Environment (CHARGE) Study . CHARGE is a population-based study led by Irva Hertz-Picciotto PhD, professor of epidemiology, and chief of the Division of Environmental and Occupational Health at University of California Davis, and one of the leaders of the research team.
CHARGE includes cases and controls matched by age, sex, and geographic location. Each of the 158 cases and 147 controls were scored for genetic deletions, duplications, and overall changes in copy number variations. Environmental exposures for each participant were determined through medical histories based on where they had lived using data from the U.S. Environmental Protection Agency (EPA) Air Quality System.
"This study used unique resources," said Hertz-Picciotto. "By mapping the homes of the mothers during their pregnancies, we were able to estimate their levels of exposure to several types of air pollutants that are monitored by the U.S. EPA. This allowed us to examine differences between cases of autism and typically developing controls in both their prenatal pollutant exposure and their total load of extra or deleted genetic material."
Evaluation of each risk factor showed that duplications, total copy-number variations, and particulate matter in the environment had the largest individual impact on risk for autism.
Ozone on its own had very little effect on risk for autism. In studies that don't take interactions between risk factors into consideration, it can be missed. Interactions amongst various other factors, even those with a large individual impact, seem to have very little overall effect on risk.
"This study shows the effect of a pollutant not previously associated with autism risk — and may be one example of how taking genomic variation into account can help us identify new risk factors for autism," said Heather Volk, assistant professor in the Department of Mental Health at the Johns Hopkins Bloomberg School of Public Health.
Selleck: "If we just look at the raw numbers, before any statistical assessment, we see a ten-fold increase in the risk of autism for individuals in the top 25 percent for level of genetic variation, and in the top 25 percent for exposure to ozone — compared to individuals in the bottom 25 percent for each of these measures."
"This increase in risk is striking, but given what we know about the complexity of diseases like autism, perhaps not surprising. It demonstrates how important it is to consider different types of risk factors for disease together, even those with small individual effects."
Researchers speculate that ozone acting as an oxidizing agent, increases copy-number variation in cells. It is known to produce reactive oxygen species (ROS), like peroxides, that stress and alter cell function. High levels of copy-number variation may indicate a compromised cell state primed for ozone damage.
Current research suggests that incidence and heterogeneity of autism spectrum disorder (ASD) symptoms may arise through a variety of exogenous and/or endogenous factors. While subject to routine clinical practice and generally considered safe, there exists speculation, though no human data, that diagnostic ultrasound may also contribute to ASD severity, supported by experimental evidence that exposure to ultrasound early in gestation could perturb brain development and alter behavior. Here we explored a modified triple hit hypothesis [Williams & Casanova, 2010] to assay for a possible relationship between the severity of ASD symptoms and (1) ultrasound exposure (2) during the first trimester of pregnancy in fetuses with a (3) genetic predisposition to ASD. We did so using retrospective analysis of data from the SSC (Simon's Simplex Collection) autism genetic repository funded by the Simons Foundation Autism Research Initiative. We found that male children with ASD, copy number variations (CNVs), and exposure to first trimester ultrasound had significantly decreased non-verbal IQ and increased repetitive behaviors relative to male children with ASD, with CNVs, and no ultrasound. These data suggest that heterogeneity in ASD symptoms may result, at least in part, from exposure to diagnostic ultrasound during early prenatal development of children with specific genetic vulnerabilities. These results also add weight to on-going concerns expressed by the FDA about non-medical use of diagnostic ultrasound during pregnancy. Autism Res 2017, 10: 472–484. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.
In addition to Selleck, Hertz-Picciotto, and Volk, the research team includes Santosh Girirajan and Molly A. Hall at Penn State; Marylyn D. Ritchie, Dokyoon Kim, Sarah Pendergrass, and Shefali S. Verma at Geisinger Heather System; Rebecca J. Schmidt, Robin L. Hansen, Yunin Ludena-Rodriguez, and Kyoungmi Kim at the University of California Davis; and Debashis Ghosh at the University of Colorado Anshutz Medical Campus. The research was supported by the U.S. National Institutes of Health, the U.S. National Institute of Environmental Health Sciences, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the U.S. Environmental Protection Agency.
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Environmental factors ( such as ozone) can interact with genetic copy number variations
to produce a higher risk for autism than expected simply from adding the two risk
factors together. A result not found by studying risk factors independently.
Image Credit: Pennsylvania State University