have long known that individual diseases are associated with genes in
specific locations of the genome. Genetics researchers at the University
of North Carolina School of Medicine now have shown definitively that a
small number of places in the human genome are associated with a large
number and variety of diseases. In particular, several diseases of aging
are associated with a locus which is more famous for its role in
this analysis, researchers at UNC Lineberger Comprehensive Cancer
Center cataloged results from several hundred human Genome-Wide
Association Studies (GWAS) from the National Human Genome Research
Institute. These results provided an unbiased means to determine if
varied different diseases mapped to common ‘hotspot’ regions of the
human genome. This analysis showed that two different genomic locations
are associated with two major subcategories of human disease.
team is interested in understanding genetic susceptibility to diseases
associated with aging, including cancer,” said PhD student William Jeck,
who was first author on the study, published in the journal Aging Cell.
team examined the large NHGRI dataset and first eliminated hereditable
traits such as eye or hair color and other non-disease traits like drug
metabolism. The group then focused on variants identified from GWAS that
contributed to actual diseases. Combining results from all of these
studies, there was enough data to arrive at statistically valid
conclusions. The team then mapped the disease associations to the
appropriate locations of the genome, counting the number of unique
diseases mapping to specific genomic regions, in order to see if
disparate diseases mapped randomly throughout the genome, or clustered
we ended up with is a very interesting distribution of disease risk
across the genome. More than 90% of the genome lacked any disease loci.
Surprisingly, however, lots of diseases mapped to two specific loci,
which soared above all of the others in terms of multi-disease risk.
The first locus at chromosome 6p21, is where the major
histocompatibility (MHC) locus resides. The MHC is critical for tissue
typing for organ and bone marrow transplantation, and was known to be an
important disease risk locus before genome-wide studies were available.
Genes at this locus determine susceptibility to a wide variety of
autoimmune diseases such as arthritis, celiac disease, Type I diabetes,
asthma, psoriasis, and lupus,” said Jeck.
second place where disease associations clustered is the INK4/ARF (or
CDKN2a) tumor suppressor locus. This area, in particular, was the
location for diseases associated with aging: atherosclerosis, heart
attacks, stroke, Type II diabetes, glaucoma and various cancers,” he
finding that INK4/ARF is associated with lots of cancer, and MHC is
associated with lots of diseases of immunity is not surprising—these
associations were known. What is surprising is the diversity of
diseases mapping to just two small places: 30% of all tested human
diseases mapped to one of these two places. This means that genotypes
at these loci determine a substantial fraction of a person’s resistance
or susceptibility to multiple independent diseases,” said Ned Sharpless,
MD, Wellcome Distinguished Professor of Cancer Research and Associate
Director of Translational Research at UNC Lineberger.
interesting finding was the apparent role of two biological processes
in multi-disease association. In addition to the MHC and INK4/ARF loci,
five less significant hotspot loci were also identified. Of the seven
total hotspot loci, however, all contained genes associated with either
immunity or cellular senescence. Cellular senescence is a permanent form
of cellular growth arrest, and it is an important means whereby normal
cells are prevented from becoming cancerous. It has been long known that
senescent cells accumulate with aging, and may cause aspects of aging.
This new analysis provides evidence that genetic differences in an
individual’s ability to regulate the immune response and activate
cellular senescence determine their susceptibility to many seemingly
call the absence of disease ‘wellness’, and our results suggest the
genetics of wellness may be much more simple than previously suspected.
Put another way, these unbiased data from about two million people
suggest that your eccentric Uncle Joe, who drank and smoked, but who
also lived to be 110 and was never sick a day in his life—well Uncle Joe
may have just been genetically fortunate at a couple of loci,” said
Siebold, PhD also worked on the research team. The study was supported
by the Burroughs Wellcome Fund and the National Institute of Aging