Autism research made to order.

Over the past decade, many studies have suggested that the genetic risk for autism is related to several genes, but identification of a known autism susceptibility gene has eluded scientists. Now, using a new statistical method known as ordered-subset analysis (OSA), researchers at the Duke University Center for Human Genetics have linked one type of autistic behavior to a specific gene (GABRB3) on chromosome 15. With this study, the researchers have both narrowed a region of interest for future autism studies and shown that OSA is an effective means for mapping disease-susceptibility genes.

"The use of OSA in autism represents just one effort to adapt an analytical strategy in a new and exciting way to maximize the information we can extract from our data," says Margaret Pericak-Vance, center director and principal investigator of the study, which was published in the March 2003 issue of the American Journal of Human Genetics.

Autism, estimated to affect some 1.5 million Americans, has been associated with a number of genes, giving rise to a multitude of variables and making the study of genetic links to autism exceedingly complex. "If only one gene contributes to a disease, all the families you study will have variations of that gene," explains Ellen Wijsman, a research professor of medicine and biostatistics at the University of Washington. "But if two or three or ten genes are involved, a very small number of families may have variations in a given gene. You may need very large sample sizes to pick up these very weak genetic signals."

Another problem arises in deciding how to group participants for statistical analysis. "When one is trying to subdivide a sample of families on the basis of a continuous covariate such as [child's] age or severity of behavior, it can be very difficult to choose and defend cut points," says Elizabeth Hauser, a statistical geneticist at the Duke center who helped develop the OSA method. Taking an example where age of onset might be analyzed as a variable, she asks, "Is the genetic effect likely to be strongest in the half of families with the youngest age of onset, or the third of families with the youngest age, or the quarter of families with the youngest age?"

Instead of comparing predefined groups, OSA ranks participants on a continuum and automatically selects the group that provides the best match, for example of a trait to a particular gene. The OSA method was built on a technique used in the mapping of the breast cancer gene BRCA1. The OSA software can be downloaded at http://www.chg.duke.edu/software/osa.html.

Children with autism can vary greatly in the behaviors they exhibit, and in their ability to communicate and interact with others. The Duke researchers narrowed their search for autism genes by focusing on genetic links to specific autism traits, including repetitive behaviors such as "insistence on sameness," a character trait defined by Duke child clinical psychologist and report coauthor Michael Cuccaro. In insistence on sameness, children exhibit repetitive compulsions and have a very difficult time adapting to change. An OSA analysis of the 221 children in the Duke study linked the subset of children with the insistence on sameness trait to the GABRB3 locus on the 15q11-q13 chromosomal region.

The GABRB3 locus is near genes that encode parts of the receptor for the inhibitory neurotransmitter [gamma]-aminobutyric acid, or GABA. This finding is consistent with previous research implicating this area of chromosome 15 with autism. The functional relationship between GABRB3 and autism is not well understood, says Cuccaro. "An intuitively appealing hypothesis is that, given the role of GABA in inhibition, a disruption of this system could result in a corresponding problem with behavioral controls."

Two other neurodevelopmental disorders, Prader-Willi syndrome and Angelman syndrome, have also been linked with damage to the same area of chromosome 15. Both of these syndromes share some symptoms with autism, including language and motor delays, learning disabilities, and behaviors such as tantrums (for Prader-Willi syndrome) and hand-flapping (for Angelman syndrome).

Research linking autism symptoms with specific genes may eventually have implications for treatment, says Cuccaro. "Individuals who have shared clinical features may also have common underlying mechanisms, which in turn may be responsive to certain types of intervention, both biological and psychosocial."

Duke researchers continue to use OSA in studies of autism and other complex diseases linked to multiple genes, including diabetes mellitus, Alzheimer disease, Parkinson disease, and heart disease. In a study of early-onset heart disease, researchers are using factors including waist circumference and lipid levels in the blood to analyze potential genetic linkages, and with Alzheimer disease, they are analyzing age of onset, says Pericak-Vance.