ARRA IMPACT REPORT:
Autism Spectrum Disorder – Genetic & Environmental Factors
Public Health Burden
Current estimates suggest that autism spectrum disorder (ASD) affects as many as 1 in 88 U.S. children.1 ASD is associated with a wide range of developmental issues, but the core symptoms are problems with social interactions and communication skills, as well as repetitive and stereotyped behaviors. Symptoms usually appear before age three, and can cause delays or problems that develop from infancy to adulthood.
Genetic Risk Factors
As with many complex disorders, the causes of ASD are generally thought to include some forms of genetic risk together with some forms of non-genetic environmental exposure. ARRA funds have been used to study an array of genetic factors.
Identification of 21 New Spontaneous Gene Mutations Associated with ASD: One team at the University of Washington sequenced DNA regions that encode for proteins (called “exomes”) to identify spontaneously occurring mutations (such as those from errors in DNA replication, spontaneous lesions, and transposable genetic elements), or mutations not found in the DNA of either parent, that contribute significantly to ASD. They sequenced exomes of 20 individuals with ASD, who had no known genetic cause for the disorder, and their parents (who did not have ASD), and subsequently identified 21 new mutations, some of which were more common in severely affected individuals. The results suggest that these spontaneous mutations may contribute substantially to the genetic basis of ASD, and show that exome sequencing of affected children and their parents is a powerful approach for identifying new candidate genes for ASD.2
Chromosomal Regions of Duplication or Deletions: Recent genetic studies have associated small duplications and deletions in regions of certain chromosomes with ASD and other neurodevelopmental disorders. ARRA-funded investigators at Beth Israel Deaconess Medical Center studied the most frequently reported chromosomal region of duplication in ASD (denoted 15q11-q13). They found that mouse models with multiple copies of a particular gene in this region developed social and communication impairments and stereotypic behaviors, which are core traits of ASD. These results provide insights into how 15q11-q13 duplications contribute to ASD and suggest a potential molecular target for intervention.3
Large Regions of Spontaneously Occurring Genetic Mutations: Recent sequencing studies have demonstrated that people with ASD are far more likely to have large de novo, or spontaneously occurring genetic mutations—sometimes a million bases of DNA that are abnormally duplicated or deleted and not found in either parent. An ARRA-supported collaboration across several institutions (the Broad Institute, Baylor College of Medicine, University of Pennsylvania, Mount Sinai School of Medicine, and Vanderbilt University) sequenced 1000 exomes of people with ASD and compared these gene sequences with those of 1000 controls. They found that while individual genes appear to confer limited risk, the aggregate effect of spontaneous coding mutations across the genome is estimated to increase the risk of ASD by 5–20-fold.4
The role of the environment in ASD has begun to receive increasing attention, and ARRA provided an excellent opportunity to boost investments in this important area of research. ARRA-funded investigators associated with a large, population-based case control study (Childhood Autism Risk from Genes and Environment, or CHARGE) have been working to examine the impact of pollutants and nutrition on ASD risk, including how environmental triggers may interact with genetic factors.
- Vehicular Traffic-related Pollutants: University of Southern California investigators, in collaboration with CHARGE, have been working to determine whether exposure to traffic-related pollution is associated with ASD. They found that children born to mothers living within 1000 meters of a major road or freeway were twice as likely to be diagnosed with ASD as those living further away. The study is the first to link exposure to vehicular pollutants with ASD risk and points the way for future research that directly measures specific traffic pollutants and their effects on physiological factors that may be causally related to ASD.5
Maternal Nutrition during Pregnancy: The CHARGE investigators at University of California, Davis, also examined associations between maternal nutrition during pregnancy and ASD. They found that mothers who reported taking prenatal vitamins both before and during the first month of pregnancy were at reduced risk of having a child with ASD. The study also reported the first gene-environment interaction in ASD, as the association between prenatal vitamin intake and ASD risk depended on the genetic makeup of the mother and child. If this finding is replicated, it will indicate an inexpensive and simple method for women to reduce ASD risk for their children.6
Contributing NIH Institutes & Centers
- Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
- National Institute of Environmental Health Sciences (NIEHS)
- National Institute of Mental Health (NIMH)
- National Institute of Neurological Disorders and Stroke (NINDS)