Using a new and powerful approach to understand the origins of
neurodegenerative disorders such as Alzheimer's disease, researchers at
Mayo Clinic in Florida are building the case that these diseases are
primarily caused by genes that are too active or not active enough,
rather than by harmful gene mutations.
In the June 7 online issue of PLoS Genetics, they report
that several hundred genes within almost 800 brain samples of patients
with Alzheimer's disease or other disorders had altered expression
levels that did not result from neurodegeneration. Many of those
variants were likely the cause.
"We now understand that disease likely develops from gene variants
that have modest effects on gene expression, and which are also found in
healthy people. But some of the variants -- elevating expression of
some genes, reducing levels of others -- combine to produce a perfect
storm that leads to dysfunction," says lead investigator Nilufer
Ertekin-Taner, M.D., Ph.D., a Mayo Clinic neurologist and
neuroscientist.
"If we can identify the genes linked to a disease that are too active
or too dormant, we might be able to define new drug targets and
therapies," she says. "That could be the case for both neurodegenerative
disease as well as disease in general."
Dr. Ertekin-Taner says no other lab has performed the extent of brain
gene expression study conducted at Mayo Clinic's Florida campus. "The
novelty, and the usefulness, of our study is the sheer number of brain
samples that we looked at and the way in which we analyzed them. These
results demonstrate the significant contribution of genetic factors that
alter brain gene expression and increase risk of disease," she says.
This form of data analysis measures gene expression levels by
quantifying the amount of RNA produced in tissue and scans the genome of
patients to identify genetic variants that associate with these levels.
Mayo researchers measured the level of 24,526 transcripts (messenger
RNA) for 18,401 genes using cerebellar autopsy tissue from 197
Alzheimer's disease patients and from 177 patients with other forms of
neurodegeneration. The researchers then validated the results by
examining the temporal cortex from 202 Alzheimer's disease patients and
from 197 with other pathologies. The difference between these samples is
that while the temporal cortex is affected by Alzheimer's disease, the
cerebellum is relatively spared.
From these analyses, the researchers identified more than 2,000
markers of altered expression in both groups of patients that were
common between the cerebellum and temporal cortex. Some of these markers
also influenced risk of human diseases, suggesting their contribution
to development of neurodegenerative and other diseases regardless of
their location in the brain.
They identified novel expression "hits" for genetic risk markers of
diseases that included progressive supranuclear palsy, Parkinson's
disease, and Paget's disease, and confirmed other known associations for
lupus, ulcerative colitis, and type 1 diabetes.
"Altered expression of brain genes can be linked to a number of diseases that affect the entire body," Dr. Ertekin-Taner says.
They then compared their eGWAS to GWAS data on Alzheimer's disease,
conducted by the federally funded Alzheimer's Disease Genetics
Consortium, to test whether some of the risk genes already identified
promote disease through altered expression.
"We found that a number of genes already linked to Alzheimer's
disease do, in fact, have altered gene expression, but we also
discovered that many of the variants in what we call the gray zone of
the GWAS -- genes whose contribution to Alzheimer's disease was
uncertain -- were also influencing brain expression levels," Dr.
Ertekin-Taner says. "That offers us new candidate risk genes to explore.
"This is a powerful approach to understanding disease," she says. "It
can find new genes that contribute to risk, as well as new genetic
pathways, and can also help us understand the function for a large
number of genes and other molecular regulators in the genome that are
implicated in very important diseases."
The study was funded in part by National Institutes of Health grants
and the Mayo Alzheimer's Disease Research Center. The complete results
are being made available to the scientific community.
Study co-authors include Fanggeng Zou, Ph.D., High Seng Chai, Curtis
Younkin, Mariet Allen, Steven Younkin, M.D., Ph.D., and Minerva
Carrasquillo, Ph.D., who also provided genotypes for the Mayo
Alzheimer's disease GWAS; Dennis Dickson, M.D., Julia Crook, Ph.D.,
Shane Pankratz, Ph.D., Neill Graff-Radford, M.D., and Ronald Petersen,
M.D., Ph.D.
Journal Reference:
- Fanggeng Zou, High Seng Chai, Curtis S. Younkin, Mariet Allen, Julia Crook, V. Shane Pankratz, Minerva M. Carrasquillo, Christopher N. Rowley, Asha A. Nair, Sumit Middha, Sooraj Maharjan, Thuy Nguyen, Li Ma, Kimberly G. Malphrus, Ryan Palusak, Sarah Lincoln, Gina Bisceglio, Constantin Georgescu, Naomi Kouri, Christopher P. Kolbert, Jin Jen, Jonathan L. Haines, Richard Mayeux, Margaret A. Pericak-Vance, Lindsay A. Farrer, Gerard D. Schellenberg, Ronald C. Petersen, Neill R. Graff-Radford, Dennis W. Dickson, Steven G. Younkin, Nilüfer Ertekin-Taner. Brain Expression Genome-Wide Association Study (eGWAS) Identifies Human Disease-Associated Variants. PLoS Genetics, 2012; 8 (6): e1002707 DOI: 10.1371/journal.pgen.1002707
Courtesy: ScienceDaily
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