Post by deborah on Feb 28, 2019 23:48:07 GMT
2.28.2019
UM Leads Largest-Ever Alzheimer’s Gene Study, Achieves Landmark Breakthroughs
Collaboration — that’s what allowed an international team of researchers to analyze information from an extraordinarily large number of people — more than 94,000 individuals — and arrive at some striking revelations about the underlying causes of Alzheimer’s disease, including five new genes that increase risk for the disease.
The meta-analysis, which combines and reevaluates data collected by four consortia that make up the International Genomic Alzheimer’s Project (IGAP), appeared in the journal Nature Genetics on February 28.
“It’s amazing how much can be accomplished by pooling resources,” said first author Brian Kunkle, Ph.D., an associate scientist at the John P. Hussman Institute for Human Genomics (HIHG) at the University of Miami Miller School of Medicine. “The ability to combine data from so many research groups gave us the power to detect new links to the causes of Alzheimer’s disease.”
This unprecedented project, funded in part by the National Institute on Aging (NIA) and other components of the National Institutes of Health (NIH), scrutinized more genetic data than any other study of Alzheimer’s disease to date. Collaborative data sharing enabled the scientists to discover five novel genetic variants or changes that influence the risk for Alzheimer’s disease.
The researchers, all IGAP members, including the lead authors, Dr. Kunkle and HIHG Director Margaret Pericak-Vance, Ph.D., at the University of Miami and Drs. Benjamin Grenier-Boley and Jean-Charles Lambert from INSERM in Lille, France, also made other landmark breakthroughs. Namely, they uncovered how the existence of specific changes (variants) in genes that bind to a protein called “tau” may affect disease development at an earlier stage than previously thought, and revealed a formerly unknown common feature between early-onset and late-onset Alzheimer’s disease (i.e. how certain proteins called amyloid precursor proteins are broken down). The latter finding suggests that some therapies developed for early-onset disease may also work for late-onset disease.
Because the combined influence of genes can differ dramatically from how each gene functions by itself, researchers in the field of genomics examine not just what the body’s instruction manuals (genes) convey independently, but how these instructions build on each other and interact with the environment. The new findings from this study support the idea that groups of genes linked to specific biological processes work in tandem to control functions that affect disease development. For example, amyloid processing, tau binding, lipid transport, inflammation, and immune response appear to be controlled by “genetic hubs.”
Once the functions of the five genes newly associated with Alzheimer’s disease — IQCK, ACE, ADAM10, ADAMTS1 and WWOX — are understood and examined in conjunction with the functions of other genes known to influence risk, scientists will be in a better position to identify where the genetic hubs of Alzheimer’s disease are clustering. Armed with these findings, researchers can look more deeply into these genetic hubs to reveal disease mechanisms and potential drug targets.
The study also revealed that rare variants — those variants that are at a frequency of less than one percent in a population — likely play an important role in Alzheimer’s disease. The researchers discovered this by showing that common risk variants (genetic variants found in more than one percent of a population) and rare risk variants for Alzheimer’s disease tend to be found in the same genes and hubs. While several rare variants have been previously linked to increased risk of the disease, this is the first study to show that many more rare risk variants exist, and they are most likely to be found in the same genes and hubs that contain common risk variants. Identifying and confirming these rare risk variants will be a significant step forward for the creation of personalized screening strategies and better informed drug development for Alzheimer’s disease.
“This is an exciting time to be studying Alzheimer’s disease, which is the most common cause of dementia in the elderly,” Dr. Pericak-Vance said. “Genes contain the body’s instruction manuals, and we now have a much better understanding of how to read the instructions related to Alzheimer’s disease as the initial step to translation to clinical care.”
Other collaborators on this study from the University of Miami include Eden R. Martin, Ph.D., Kara L. Hamilton-Nelson, MPH, Gary W. Beecham, Ph.D., John R. Gilbert, Ph.D., Susan Slifer, MS, Michael L. Cuccaro, Ph.D., and Jeffery Vance, M.D., Ph.D. (all at HIHG), as well as Elizabeth A. Crocco, M.D., and Amanda J. Myers, Ph.D., from the Department of Psychiatry and Behavioral Sciences, and Deborah C. Mash, Ph.D., professor emeritus, from the Department of Neurology.
UM Leads Largest-Ever Alzheimer’s Gene Study, Achieves Landmark Breakthroughs
Collaboration — that’s what allowed an international team of researchers to analyze information from an extraordinarily large number of people — more than 94,000 individuals — and arrive at some striking revelations about the underlying causes of Alzheimer’s disease, including five new genes that increase risk for the disease.
The meta-analysis, which combines and reevaluates data collected by four consortia that make up the International Genomic Alzheimer’s Project (IGAP), appeared in the journal Nature Genetics on February 28.
“It’s amazing how much can be accomplished by pooling resources,” said first author Brian Kunkle, Ph.D., an associate scientist at the John P. Hussman Institute for Human Genomics (HIHG) at the University of Miami Miller School of Medicine. “The ability to combine data from so many research groups gave us the power to detect new links to the causes of Alzheimer’s disease.”
This unprecedented project, funded in part by the National Institute on Aging (NIA) and other components of the National Institutes of Health (NIH), scrutinized more genetic data than any other study of Alzheimer’s disease to date. Collaborative data sharing enabled the scientists to discover five novel genetic variants or changes that influence the risk for Alzheimer’s disease.
The researchers, all IGAP members, including the lead authors, Dr. Kunkle and HIHG Director Margaret Pericak-Vance, Ph.D., at the University of Miami and Drs. Benjamin Grenier-Boley and Jean-Charles Lambert from INSERM in Lille, France, also made other landmark breakthroughs. Namely, they uncovered how the existence of specific changes (variants) in genes that bind to a protein called “tau” may affect disease development at an earlier stage than previously thought, and revealed a formerly unknown common feature between early-onset and late-onset Alzheimer’s disease (i.e. how certain proteins called amyloid precursor proteins are broken down). The latter finding suggests that some therapies developed for early-onset disease may also work for late-onset disease.
Because the combined influence of genes can differ dramatically from how each gene functions by itself, researchers in the field of genomics examine not just what the body’s instruction manuals (genes) convey independently, but how these instructions build on each other and interact with the environment. The new findings from this study support the idea that groups of genes linked to specific biological processes work in tandem to control functions that affect disease development. For example, amyloid processing, tau binding, lipid transport, inflammation, and immune response appear to be controlled by “genetic hubs.”
Once the functions of the five genes newly associated with Alzheimer’s disease — IQCK, ACE, ADAM10, ADAMTS1 and WWOX — are understood and examined in conjunction with the functions of other genes known to influence risk, scientists will be in a better position to identify where the genetic hubs of Alzheimer’s disease are clustering. Armed with these findings, researchers can look more deeply into these genetic hubs to reveal disease mechanisms and potential drug targets.
The study also revealed that rare variants — those variants that are at a frequency of less than one percent in a population — likely play an important role in Alzheimer’s disease. The researchers discovered this by showing that common risk variants (genetic variants found in more than one percent of a population) and rare risk variants for Alzheimer’s disease tend to be found in the same genes and hubs. While several rare variants have been previously linked to increased risk of the disease, this is the first study to show that many more rare risk variants exist, and they are most likely to be found in the same genes and hubs that contain common risk variants. Identifying and confirming these rare risk variants will be a significant step forward for the creation of personalized screening strategies and better informed drug development for Alzheimer’s disease.
“This is an exciting time to be studying Alzheimer’s disease, which is the most common cause of dementia in the elderly,” Dr. Pericak-Vance said. “Genes contain the body’s instruction manuals, and we now have a much better understanding of how to read the instructions related to Alzheimer’s disease as the initial step to translation to clinical care.”
Other collaborators on this study from the University of Miami include Eden R. Martin, Ph.D., Kara L. Hamilton-Nelson, MPH, Gary W. Beecham, Ph.D., John R. Gilbert, Ph.D., Susan Slifer, MS, Michael L. Cuccaro, Ph.D., and Jeffery Vance, M.D., Ph.D. (all at HIHG), as well as Elizabeth A. Crocco, M.D., and Amanda J. Myers, Ph.D., from the Department of Psychiatry and Behavioral Sciences, and Deborah C. Mash, Ph.D., professor emeritus, from the Department of Neurology.