6 | Advancing knowledge
COMING uP TRuMPS CLOSE ASSOCIATION
Genome-wide studies have identified individual effect. Indeed, a significant Follow-up of genome-wide analyses
hundreds of disease associations. fraction of the genetic contribution to can reveal disease mechanisms –
disease remains unaccounted for. and even possible environmental
Set up in 2007, the Wellcome Trust Case Furthermore, only rarely has the precise influences on disease.
Control Consortium has pioneered a new genetic risk factor (the ‘causal variant’)
wave of large-scale, high-throughput been identified. In some cases, a single Genome-wide studies identify
genome-wide association studies. These association may actually be a composite associations between a disease and a
studies have identified several hundred of several genetic variants lying close genetic marker, but only rarely is that
genetic sites influencing (‘associated together (as seen in rheumatoid arthritis).
marker itself the factor affecting risk.
with’) common diseases. Looking More likely, it just happens to be close to
forward, next-generation sequencing To winkle out the remaining genetic (and hence inherited with) the true culprit.
technologies are providing the tools to factors – and to move from an At the Cambridge Institute of Medical
identify many more. association to a causal variant – a much Research, Linda Wicker and John Todd’s
more detailed view of human genetic groups are homing in on ‘causal variants’
Genome-wide studies have continued to variation is needed. This is the goal in type 1 diabetes.
develop at an astonishing rate. As well as of the 1000 Genomes Project, which
being applied to a wider range of is using next-generation sequencing One way to connect the two is to look for
conditions, such as Alzheimer’s disease,
technologies to provide a high-resolution nearby genes that could plausibly affect
they are also being used to explore view of variation. A stepping-stone a disease. As type 1 diabetes is caused
physiological traits relevant to disease, towards this goal was the sequencing by a self-directed immune response,
such as blood lipid
or blood glucose
of the first individual African genome, in Linda Wicker, John Todd and colleagues
levels or blood pressure.
Extensive a collaboration between the Wellcome focused on a likely candidate gene
international collaborations have enabled Trust Sanger Institute and the next- (encoding a protein known as IL2RA
data to be pooled, which has enabled generation sequencing company or CD25) involved in immune system
even more risk loci to be identified (see Illumina.
With new statistical and methodological Genetic variants around the IL2RA gene
While each individual association has tools also being developed (see page 33), affected how much IL2RA protein was
value, collectively they may shed further these resources will continue to drive present on the surface of a key set of
light on disease processes. Studies of rapid progress in the genetic dissection immune cells. Moreover, the variants
Crohn’s disease, for example, implicated of common diseases. previously linked to diabetes had the
autophagy (breakdown and disposal of greatest effect on IL2RA levels. Hence,
cell structures) as an important disease
This research was supported by the Wellcome Trust
variation in IL2RA levels affecting the
Studies of autoimmune
and other funders.
function of these immune cells is likely to
conditions have revealed that many risk
1 Harold D et al. Nat Genet 2009;41(10):1088–93.
underlie the increased risk of diabetes.
loci are shared between diseases.
Erratum in: Nat Genet 2009;41(10):1156.
type 1 diabetes, genetic discoveries are
2 Prokopenko I et al. Nat Genet 2009;41(1):77–81.
Adopting a different strategy, John Todd,
shedding light on environmental
3 Soranzo N et al. Nat Genet 2009;41(11):1182–90.
Sergey Nejentsev and collaborators
influences on disease (see right). 4 Newton-Cheh C et al. Nat Genet 2009;41(6):666–76. at Roche-454 used next-generation
5 Parkes M et al. Nat Genet 2007;39(7):830–2.
techniques to sequence ten genes
The studies also provide clues to the implicated in type 1 diabetes in nearly
6 Barton A et al. Hum Mol Genet 2009;18(13):2518–22.
‘genetic architecture’ of disease. Most 1000 patients and controls.
conditions are influenced by a large
7 Orozco G et al. Hum Mol Genet 2009;18(14):2693–9.
number of genes, mostly of small
8 Bentley DR et al. Nature 2008;456(7218):53–9.
Millions of samples can be genotyped in high-throughput facilities.
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