The research was led by Margaret A. Pericak-Vance, Ph.D., Director of the Hussman Institute for Human Genomics, and Stephan Züchner M.D., Interim Chair of the Dr. John T. Macdonald Foundation Department of Human Genetics. Dr. Pericak-Vance’s post-doctoral fellow, Martin A. Kohli, Ph.D., was the first author on the paper, Repeat expansions in the C9ORF72 gene contribute to Alzheimer’s disease in Caucasians.
“We are excited about this research finding because it solidifies that rare genetic variants can contribute to risk in late onset Alzheimer’s disease,” Pericak-Vance said.
Previously, researchers identified a stretch in DNA, in this case an intronic hexanucleotide repeat expansion in the C9ORF72 gene, which accounted for a significant portion of families affected by neurodegenerative disorders, frontotemporal dementia and amyotrophic lateral sclerosis (ALS). Healthy individuals appear to have 0 to about 20 repetitions of this stretch of DNA, whereas at-risk patients have more than 30 expansions, up to a thousand. The pathogenic range of expansions interferes with expression and thus proper functioning of the C9ORF72 gene.
Since causes for neurodegenerative disorders have been found to overlap, researchers in this study hypothesized that DNA stretches in the C9ORF72 gene could also cause Alzheimer’s disease in some individuals. They examined more than 1,100 patients with Alzheimer’s disease and found that approximately one percent of the cases also had large expansions in the C9ORF72 gene, whereas none of the controls had large expansions. In contrast, no large expansions were detected in patients of African-American ethnicity. Therefore, repeat expansions in the C9ORF72 gene appear to be a new cause for Alzheimer’s disease, but only in Caucasians.
Moreover, these ethnic differences in the prevalence of C9ORF72 expansion carriers may provide further insight into the underlying molecular mechanisms of this genetic cause of neurodegenerative disease in both Caucasians and African-Americans.
Other UM researchers included Krista John-Williams, M.S., research associate; Patrice Whitehead, B.S., director of research laboratory; Kara Hamilton, M.P.H., project manager of research support; Gary Beecham, Ph.D., assistant professor of human genetics; Eden R. Martin, Ph.D., professor of human genetics; John Gilbert, Ph.D., professor of human genetics; Michael Benatar, M.D., Ph.D., associate professor of neurology; Clinton Wright, M.D., associate professor of neurology; Deborah Mash, Ph.D., professor of neurology; Regina M. Carney, M.D., assistant professor of clinical psychiatry and behavioral sciences; and Elizabeth Crocco, M.D., assistant professor of clinical psychiatry and behavioral sciences.
They were joined by Harry E. Gwirtzman, M.D. (Vanderbilt), Rosalyn Lang, Ph.D. (North Carolina A&T), Gary W. Small, M.D. (UCLA), Goldie Byrd, Ph.D. (North Carolina A&T), and Jonathan L. Haines, Ph.D. (Vanderbilt).
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