A major goal of autism research is to identify the underlying genetic variants that contribute to risk of the disorder. Knowledge of these genetic variants may yield insight into how and why autism symptoms develop, and ultimately provide a list of potential therapeutic targets.

Four times as many males as females are afflicted with autism. Although there is much speculation about this sex bias, there have not been many well-powered studies designed to identify female genetic susceptibilities and differentiate them from male risk factors. Lauren Weiss and her colleagues at the University of California, San Francisco, set out to map the difference between male and female autism at the level of DNA. Understanding sexual dimorphism at this level may suggest ways to reduce autism risk for males and females.

People with autism spectrum disorders often lack self-awareness, making it difficult for them to interact and empathize with others. Using new genomics methods to study the neurons that are active during self-awareness and empathy, John Allman and Barbara Wold of the California Institute of Technology are learning how these processes are different in people with autism.

Studies focusing on specific genes have made limited progress in unraveling the complex genetics of autism spectrum disorders. Evan Eichler and his colleagues at the University of Washington plan a broad and systematic approach to uncover autism-linked genes by scouring the fragile regions of DNA for sporadic, non-inherited deletions or duplications.

Based on a genome-wide association study, Mark Daly of Massachusetts General Hospital and his colleagues reported in 2008 that genetic variation in the 16p11.2 chromosomal region is a major risk factor for autism. Daly and colleagues also uncovered more than 100 other rare genetic variations that appear to contribute to risk of autism, but these polymorphisms need further confirmation to prove an association with the disorder. Taking advantage of the SFARI Simplex Collection, the researchers plan to intensively sequence the implicated regions to find rare point mutations that would not be detectable using past or current genome scanning techniques.

Advanced maternal and paternal age have been reported as risk factors for autism spectrum disorders. In general, the genetic quality of eggs and sperm declines over time, reducing the chance of older parents to produce normal offspring. Copy-number variation (CNV) — a type of genetic alteration commonly associated with autism spectrum disorder — is thought to be one of the most common problems with the quality of eggs or sperm in older individuals.

Autism spectrum disorders are heritable, and chromosomal defects are thought to play a role in their development. In a 2008 study, a group of researchers, including James F. Gusella of Massachusetts General Hospital, discovered that a stretch of DNA containing several genes is missing from chromosome 16 in about one percent of people affected or suspected to be affected with autism. The researchers hope to identify the specific genes located in this chromosomal region that play a role in causing autism.

Small variations in the DNA sequence of a gene, called polymorphisms, are known to have an impact on normal and disease phenotypes. Some polymorphisms change the length or makeup of the resulting protein, whereas others interfere with binding sites for molecules that regulate the gene’s expression.

Analyzing genetics using the tissues of people with autism can provide deeper insight into the disorder than performing genetic techniques on DNA samples alone. Arthur Beaudet and his colleagues at Baylor College of Medicine in Houston propose two projects that examine autism genetics in the context of the physiology of the disorder.

For years, autism has been noted in individuals with tuberous sclerosis, leading researchers to speculate that the two disorders may develop after troubles in the same biological pathway. Vijaya Ramesh and her colleagues at Massachusetts General Hospital are pursuing this lead by investigating whether genes linked to tuberous sclerosis are also associated with autism spectrum disorders.