Common Genetic Factors That Affect Autism
Risk Are Identified
Breakthrough in understanding the disorder’s causes

Pericak-Vance and her collaborator, Jonathan L. Haines, Ph.D., at Vanderbilt University Medical Center, joined the results of their study with those of Hakon Hakonarson, M.D., Ph.D., from Children’s Hospital of Philadelphia.

Senior members of the University of Miami and Vanderbilt autism genetics research team, from left, are John R. Gilbert, Ph.D., Deqiong Ma, M.D., Ph.D., Margaret A. Pericak-Vance, Ph.D., Jonathan L. Haines, Ph.D., and Michael L. Cuccaro, Ph.D.

The study included investigators from more than a dozen sites and participation of more than 10,000 subjects, including individuals with autism spectrum disorder, their family members, and other volunteers from across the United States.

“Each research team conducted a genome-wide association study of individuals with autism and controls, and found a significant association between autism and a region on chromosome 5 that is near two genes known as CDH9 and CDH10,” says Haines, lead investigator of the research team from Vanderbilt and director of the Vanderbilt Center for Human Genetics Research. “Both genes encode cadherins, which are cell surface proteins thought to be important for establishing connections between cells in the developing brain and are candidate genes that may contribute to autism.”

“Although no single gene is responsible for autism, cadherin is one of several proteins that affect the stability and maturation of nerve synapses in the brain. Therefore, this is an intriguing candidate for this region,” says John P. Hussman, Ph.D., one of the co-investigators in the research. “This discovery is important not only in its own right, but also because it offers important clues about specific biological processes we should investigate.”

Since individuals with autism are so diverse, some researchers believed a common risk variant would never be found, but the advent of genome-wide technology changed everything. “We’ve known that technology would evolve to where identification of the hardest-to-find genetic risk variants would be possible,” says Pericak-Vance.

Autism is among a spectrum of disorders and is a neurodevelopmental disorder characterized by three primary areas of impairment: social interaction, communication, and restricted and repetitive patterns of interest or behavior. Recent prevalence studies suggest that autism spectrum disorders may affect as many as 1 in 150 children in the United States, making it one of the most common neurodevelopmental disorders.

The study published in Nature reflects the collaborative efforts of research teams from the Miller School of Medicine, Vanderbilt, Children’s Hospital of Philadelphia, the University of Washington in Seattle, and the University of California, Los Angeles. The institutions combined resources and data sets to achieve the genome-wide significant results.

An independent publication in the Annals of Human Genetics details all the findings from the complete genome-wide study conducted by the University of Miami and Vanderbilt Medical Center on their independent data sets. Summary results from the candidate region on chromosome 5 were included in the Nature publication, as they further support the overall finding. Deqiong Ma, M.D., Ph.D., is co-first author of both publications; other key authors on both publications are Michael L. Cuccaro, Ph.D., John R. Gilbert, Ph.D., and Daria Salyakina, Ph.D., all from the Miami Institute for Human Genomics.

Alzheimer’s Findings

A project that represents one of the first essential steps in applying modern genomic approaches to complex diseases has identified nine genes that may increase susceptibility for Alzheimer’s disease and confirmed a region on chromosome 12q long believed to harbor an Alzheimer’s risk gene.

The findings, by researchers at the Miller School led by Margaret A. Pericak-Vance, Ph.D., and Jonathan L. Haines, Ph.D., at Vanderbilt University Medical Center, appeared in the January issue of the American Journal of Human Genetics.

A research team at the Miller School’s Miami Institute for Human Genomics and the Vanderbilt Center for Human Genetics Research performed a genome-wide association study using state-of-the-art genotyping technology that allows scientists to interrogate 550,000 genetic variations in approximately 500 people with Alzheimer’s disease and 500 people without the disease. The results were validated in an independent data set.

“Results from this study open the door for increased understanding of this important neurological disorder,” says Pericak-Vance, director of the Miami Institute for Human Genomics and the Dr. John T. Macdonald Foundation Professor of Human Genomics. “We now have exciting new directions to explore.”

The findings show that the amyloid precursor protein, accepted as a risk gene for early-onset Alzheimer’s disease, is also involved in late-onset Alzheimer’s disease. The study also provides evidence of a risk locus at 12q13. Chromosome 12 has been of intense interest to geneticists in search of Alzheimer’s risk genes. The locus implicated by this study is in close proximity to the vitamin D3 receptor gene. Low vitamin D levels have been reported in patients with cognitive impairment and Alzheimer’s disease. A variation in the vitamin D3 receptor gene that causes low vitamin D levels may also increase risk for Alzheimer’s disease.

The identification of new Alzheimer’s disease genes may lead to a better understanding of the complex causes of the disease, improved diagnostic tools, enhanced preventive measures, and new targets for treatment.

Other key investigators include John R. Gilbert, Ph.D., Eden R. Martin, Ph.D., Gary W. Beecham, Ph.D., and Michael A. Slifer, M.D., Ph.D., all of the Miami Institute for Human Genomics.

Pericak-Vance to Co-Lead Analysis on Alzheimer’s Genome-Wide Study

Genetic research on Alzheimer’s disease at the Miller School has received a big boost from the National Institutes of Health. The National Institute on Aging has awarded an $18.3 million five-year grant to conduct a multi-center genome-wide association study to identify genes that may affect risk for the disease. Margaret A. Pericak-Vance, Ph.D., will co-lead with Lindsay Farrer, Ph.D., of Boston University, the genetic analysis efforts on the project. The study’s principal investigator is Gerard Schellenberg, Ph.D., from the University of Pennsylvania School of Medicine.