Essential Cell Biology 5th edition

Exploring Human Genetics
685
Such linkage analyses are usually carried out in families
that are particularly prone to a disorder—the larger
the family, the better. And the method works best where
there is a simple cause-and-effect relationship, such that
a particular mutant gene directly and reliably causes the
disorder—as is the case, for example, for the mutant
gene that causes cystic fibrosis. But most common disorders
are not like this. Instead, many factors affect the
disease risk—some genetic, some environmental, some
just a matter of chance. For such conditions, a different
approach is needed to identify risk genes.
Making associations
Genome-wide association studies (GWAS, for short) allow
us to discover common genetic variants that affect the
risk for a common disease, even if each variant alters
susceptibility only slightly. Because mutations that
destroy the activity of a key gene are likely to have a
disastrous effect on the fitness of the mutant individual,
they tend to be eliminated from the population by natural
selection and so are rarely seen. Genetic variants
that alter a gene’s function only slightly, on the other
hand, are much more common. By tracking down these
common variants, or polymorphisms, we can sniff out
some of the genes that contribute to the biology of common
diseases.
GWAS rely on genetic markers, such as SNPs, that are
located throughout the genome to compare directly the
DNA sequences of two populations: individuals who
have a particular disease and those who do not. The
approach identifies SNPs that are present in the people
who have the disease more often than would be
expected by chance.
Consider the case of age-related macular degeneration
(AMD), a degenerative disorder of the retina that is
a leading cause of blindness in the elderly. To search
for genetic variations that are associated with AMD,
researchers looked at a panel of just over 100,000 SNPs
that spanned the genome. They determined the nucleotide
sequence at each of these SNPs in 96 people who
had AMD, and 50 who did not. Among the 100,000 SNPs,
they discovered that one particular SNP was present
significantly more often in the individuals who had the
disease (Figure 19−40).
The SNP is located in a gene called Cfh (complement factor
H). But it falls within one of the gene’s introns and
appears unlikely to have any effect on the protein product.
This SNP itself, therefore, did not seem likely to be
the cause of the increase in susceptibility to AMD. But
it focused the researchers’ attention on the Cfh gene.
So they resequenced the region to look for additional
polymorphisms that might also be inherited more often
by people with AMD, along with the SNP that they had
already identified. They discovered three variants that
change the amino acid sequence of the Cfh protein.
One substitutes a histidine for a tyrosine at one particular
place in the protein, and it was strongly associated
with the disease (and almost always coupled with the
original SNP that had put the researchers on the track
of the Cfh gene). Individuals who carried two copies of
this risky allele were five to seven times more likely to
develop AMD than those who harbored a different allele
of the Cfh gene.
Several other research teams, using a similar genetic
association approach, have also pointed to Cfh variants
as increasing the likelihood of developing AMD, making
it almost certain that the Cfh gene has something
to do with the biology of the disease. The Cfh protein is
part of the complement system, an important component
of immunity; the protein helps prevent the system
from becoming overactive, a condition that can lead
to inflammation and tissue damage. Interestingly, the
environmental risk factors associated with the disease—
smoking, obesity, and age—also affect inflammation and
the activity of the complement system. Thus, whatever
the detailed mechanism by which the Cfh gene influences
the risk of AMD, the finding that complement is
critical could lead to new tests for the early diagnosis
of the disorder, as well as potential new avenues for
treatment.
strength of correlation
0
SIGNIFICANT
NOT SIGNIFICANT
50,000
SNP location number
100,000
Figure 19−40 Genome-wide association studies identify
DNA variations that are significantly more frequent in people
with age-related macular degeneration (AMD). In this study,
scientists examined more than 100,000 SNPs in each of 146
people. The x-axis of the graph shows the relative position of
each SNP in the genome, starting at the left with the SNPs on
Chromosome 1. The y-axis ECB5 e19.40/19.40
shows the strength of each SNP’s
observed correlation with AMD. The blue region indicates a cutoff
level for statistical significance, corresponding to a probability of
less than 5% of finding that strength of correlation by pure chance
anywhere among the whole set of 100,000 tested SNPs. The SNP
marked in red is the one that led the way to the relevant gene,
Cfh. The initial association of the other prominent SNP (black)
with the disease was rendered insignificant when additional
sequencing at that site was performed. (Adapted from R.J. Klein
et al., Science 308:385–389, 2005.)