A Revolution in R&D

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DISEASE GENETICS—VARIOUS APPROACHES TO VARIANTS
When disease genetics is used to identify or test
variant genes, the investigation can take a variety of
forms. There are three key dimensions in the design
of such an investigation: narrow/broad, linkage/association,
and direct/indirect. These dimensions all
have a bearing on cost and the chances of success.
First, researchers can examine some of the genes (in
a narrow study, or candidate-gene study) or all of
the genes (in a broad study, or genome-wide scan).
Second, these genes can be examined through inheritance
patterns in families prone to the disease (in a
linkage study) or by comparing individual patients
with healthy individuals in the population at large (in
an association study).
Finally, within association studies, each variant gene
can be studied directly or indirectly: researchers can
test each variant individually for any involvement in
the disease (in a direct study) or test clusters of
closely positioned variants for the presence of a culprit
among them (in an indirect study).
The earliest disease genetics investigations, conducted
prior to the 1980s, were association studies,
and direct, and as narrow as could be—studying just
a single gene, which had been selected on the basis
of biological knowledge about disease mechanisms.
The researcher would seek polymorphisms in the
gene, and compare their frequencies in patients and
controls. This early approach did achieve some
notable successes, including, in 1956, the first discovery
of an inherited genetic variation found to
cause disease—the variant underlying sickle cell
anemia. The approach had a serious limitation, however:
it allowed very few genes to be examined, and
it required a prior hypothesis.
In the 1980s and 1990s, attention turned to families
showing an inherited pattern of disease. The
investigations took the form of broad linkage studies,
and were tremendously successful in identifying
some genes responsible for single-gene disorders,
notably the cystic fibrosis gene in 1989. Such studies,
being genome-wide, were now unbiased and
comprehensive. But the actual identification of
genes remained a slow, painstaking laboratory
process. So the early versions of such studies were
really suitable only for monogenic diseases. Hopes
were raised in the early 1990s, when companies
such as Millennium, Sequana, and Myriad were set
up to develop and exploit these techniques in the
quest to identify the genes implicated in common
polygenic diseases. Their initiative seems to be
stalled at the moment: although the localizing of
disease-related genes has become more efficient,
the actual locating of them remains discouragingly
difficult. That task would be better suited to association
studies.
Given the limitations in genome-wide linkage studies,
association studies have recently come back into
fashion, fortified by the efforts of the Human
Genome Project, Celera, and the SNP Consortium.
These studies have high-throughput technologies to
undergird them, as well as comprehensive databases
of gene sequences and SNPs.
Of the two possible approaches here, direct and indirect,
the former looks like a very formidable task.
The researcher conducting a direct association study,
and aiming to find the actual polymorphism underlying
the specified disease, is confronted by the entire
set of common variants in the genome—expected to
number some ten million. To examine such a horde
of variants with current technology would be inordinately
time-consuming and expensive.
Hence the hopes—and funds—now being invested in
indirect studies. Since variants in close proximity
tend to form clusters (known as haplotypes), it may
be possible to track down the disease-related polymorphisms
using only a small proportion of all
SNPs. In light of recent research findings, indirect
association studies of this kind do look practicable,
if not quite imminent.