Researchers at the University of Miami Miller School of Medicine led by Margaret A. Pericak-Vance, Ph.D. (pictured), and Jonathan L. Haines, Ph.D. at Vanderbilt University Medical Center, have 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. This project represents the first essential step in the application of modern genomic approaches to complex diseases and is one of four studies of its kind.
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 thousand genetic variations in approximately 500 people with Alzheimer’s disease and 500 people without the disease. The results were validated in an independent dataset.
“Results from this study open the door for increased understanding of this important neurological disorder,” said Dr. 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. According to Dr. Haines, “The vitamin D3 receptor finding on chromosome 12 is really exciting because it implicates a potential biological pathway that has been of interest in neurological disorders.”
For the past decade, Alzheimer’s disease genetics has been at an impasse. In the early 1990s, Dr. Pericak-Vance’s discovery of the association of apolipoprotein E with Alzheimer’s disease gave hope that the genetic etiology of a host of common diseases would rapidly unravel. Scientists were able to identify genes of large effect, because they are present in a great enough portion of the population to be detected with available technologies. Disease genes present in smaller portions of the population, however, could not be confirmed.
Genome-wide association studies have improved researchers’ ability to find disease genes of smaller or more moderate effect. Thanks to this powerful new tool, there will be several new candidate genes to pursue. “Data from the Miami Institute for Human Genomics genome-wide association study will invigorate the field and form a foundation for future investigations into the genetics of Alzheimer’s disease,” said Pericak-Vance. “We are now closely studying a number of candidate genes associated with Alzheimer’s risk in our data.”
The identification of new Alzheimer disease genes may lead to a better understanding of the complex causes of Alzheimer’s disease and lead to improved diagnostic tools, enhanced preventive measures, and find new targets for treatment.
Illustration: University of Miami Miller School of Medicine.
University of Miami Miller School of Medicine News Release (12/31/08)
Science Daily (01/05/09)
Medical News Today (01/06/09)
US News & World Report (01/07/09)
Abstract (American Journal of Human Genetics; Vol. 84, Issue 1, 35-43 (12/31/08))