Coming up trumps: Genome-wide association studies
Set up in 2007, the Wellcome Trust Case Control Consortium has pioneered a new wave of large-scale, high-throughput genome-wide association studies. These studies have identified several hundred genetic sites influencing ('associated with') common diseases. Looking forward, next-generation sequencing technologies are providing the tools to identify many more.
Genome-wide studies have continued to develop at an astonishing rate. As well as being applied to a wider range of conditions, such as Alzheimer's disease (ref. 1), they are also being used to explore physiological traits relevant to disease, such as blood lipid (ref. 2) or blood glucose (ref. 3) levels or blood pressure (ref. 4). Extensive international collaborations have enabled data to be pooled, which has enabled even more risk loci to be identified.
While each individual association has value, collectively they may shed further light on disease processes. Studies of Crohn's disease, for example, implicated autophagy (breakdown and disposal of cell structures) as an important disease process (ref. 5). Studies of autoimmune conditions have revealed that many risk loci are shared between diseases (ref. 6). In type 1 diabetes, genetic discoveries are shedding light on environmental influences on disease.
The studies also provide clues to the 'genetic architecture' of disease. Most conditions are influenced by a large number of genes, mostly of small individual effect. Indeed, a significant fraction of the genetic contribution to disease remains unaccounted for.
Furthermore, only rarely has the precise genetic risk factor (the 'causal variant') been identified. In some cases, a single association may actually be a composite of several genetic variants lying close together, as seen in rheumatoid arthritis (ref. 7).
To winkle out the remaining genetic factors - and to move from an association to a causal variant - a much more detailed view of human genetic variation is needed. This is the goal of the 1000 Genomes Project, which is using next-generation sequencing technologies to provide a high-resolution view of variation. A stepping-stone towards this goal was the sequencing of the first individual African genome, in a collaboration between the Wellcome Trust Sanger Institute and the next-generation sequencing company Illumina (ref. 8).
With new statistical and methodological tools also being developed, these resources will continue to drive rapid progress in the genetic dissection of common diseases.
This research was supported by the Wellcome Trust and other funders.
Image: Millions of samples can be genotyped in high-throughput facilities.
References
1 Harold D et al. Nat Genet 2009;41(10):1088-93. Erratum in: Nat Genet 2009;41(10):1156.
2 Prokopenko I et al. Nat Genet 2009;41(1):77-81.
3 Soranzo N et al. Nat Genet 2009;41(11):1182-90.
4 Newton-Cheh C et al. Nat Genet 2009;41(6):666-76.
5 Parkes M et al. Nat Genet 2007;39(7):830-2.
6 Barton A et al. Hum Mol Genet 2009;18(13):2518-22.
7 Orozco G et al. Hum Mol Genet 2009;18(14):2693-9.
8 Bentley DR et al. Nature 2008;456(7218):53-9.