Miller School researchers played a key role in the largest international Alzheimer’s disease genetics collaboration to date, which identified 11 new regions of the genome that contribute to late-onset Alzheimer’s disease, doubling the number of potential genetics-based therapeutic targets to investigate. Published October 27 in Nature Genetics, the study gives a broader view of the genetic factors contributing to Alzheimer’s and expands the understanding of the disease to new areas, including the immune system, where a genetic overlap with other neurodegenerative diseases, including multiple sclerosis and Parkinson’s disease, was identified.
In 2011, the world’s four largest research consortia on the genetics of Alzheimer’s disease joined efforts to discover and map the genes that contribute to Alzheimer’s, forming the International Genomics of Alzheimer’s Project (IGAP). The team collected genetic information from 25,500 Alzheimer’s disease patients and 49,038 controls from 15 countries to perform this two-stage meta-analysis that resulted in the discovery of 11 new genes in addition to those already known, and the identification of 13 other genes, yet to be validated.
Margaret A. Pericak-Vance, Ph.D., the Dr. John T. Macdonald Foundation Professor of Human Genomics and Director of the John P. Hussman Institute for Human Genomics at the Miller School, and Lindsay A. Farrer, Ph.D., from Boston University, led the analysis teams for the American Alzheimer’s Disease Genetics Consortium, which includes nearly all of the nation’s researchers working on the genetics of Alzheimer’s, as well as many investigators and resources of the 29 federally funded Alzheimer’s Disease Centers. The Hussman Institute’s Gary Beecham, Ph.D., assistant professor of human genetics; Eden R. Martin, Ph.D., professor of human genetics; John R. Gilbert, Ph.D., professor of human genetics; Kara Hamilton-Nelson, M.S., project manager for research support; and Brian Kunkle, Ph.D., postdoctoral associate, also contributed to the analysis and the study.
“This work demonstrates the enormous impact that global collaborations can have on genetic research. In less than three years since the International Genomics of Alzheimer’s Project formed, the IGAP team has identified more genes than had been identified in the previous 20 years,” said Miller School Dean Pascal J. Goldschmidt, M.D. “This is a significant step forward in unlocking the genetic code of Alzheimer’s, which began in 1993 with Dr. Pericak-Vance’s discovery of apolipoprotein E as the major susceptibility gene of late-onset Alzheimer’s disease.”
Several of the genes the researchers identified confirmed known biological pathways of Alzheimer’s disease, including the role of the amyloid (SORL1, CASS4) and tau (CASS4, FERMT2) pathways. Newly discovered genes involved in the immune response and inflammation (HLA-DRB5/DRB1, INPP5D, MEF2C) reinforced a pathway implied by previous work (on CR1, TREM2). Additional genes related to cell migration (PTK2B), lipid transport and endocytosis (SORL1) also were confirmed, and new hypotheses emerged related to hippocampal synaptic function (MEF2C, PTK2B), the cytoskeleton and axonal transport (CELF1, NME8, CASS4), as well as myeloid and microglial cell functions (INPP5D).
One of the more significant new associations was found in the HLA-DRB5/DRB1 region, one of the most complex parts of the genome, which plays a role in the immune system and inflammatory response. It also has been associated with multiple sclerosis and Parkinson’s disease, suggesting that the diseases where abnormal proteins accumulate in the brain may have a common mechanism involved, and possibly a common drug target.
“The discovery of novel pathways is very encouraging considering the limited success of Alzheimer’s disease drugs tested so far,” Pericak-Vance said. “Our findings bring us closer toward identifying new drug targets for Alzheimer’s and other neurodegenerative diseases. We’ll continue to expand and analyze our data set with this incredible group so that we can better understand the genetic influences on this devastating disease, and find new medical and therapeutic interventions.”
In addition to the Hussman team, Amanda Meyers, Ph.D., associate professor of psychiatry and behavioral sciences, contributed to the study.
The IGAP includes contributions from the Alzheimer’s Disease Genetics Consortium (ADGC) in the United States, which is led by Gerard Schellenberg, Ph.D., Perelman School of Medicine at the University of Pennsylvania; the European Alzheimer’s Disease Initiative in France, led by Philippe Amouyel, M.D., Ph.D., at the Institute Pasteur de Lille and Lille University; the Genetic and Environmental Risk in Alzheimer’s Disease from the United Kingdom, led by Julie Williams, Ph.D., at Cardiff University; the neurology subgroup of the Cohorts for Heart and Aging in Genomic Epidemiology, led by Sudha Seshadri, M.D., at Boston University School of Medicine; as well as teams from the University of Miami, Vanderbilt University, and Columbia University in the United States, among others.
The National Institute on Aging provided funding for the ADGC (U01 AG032984, R01 AG033193), and the Alzheimer’s Association provided crucial support to make this international collaboration possible.
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