Genome-wide association studies
9 February 2009
Genome-wide association studies are taking advantage of high-throughput genotyping techniques to screen the entire genome of large numbers of individuals, to identify sites in the genome that may be contributing to a disease. This year saw a whole host of studies published dissecting conditions as varied as osteoporosis, ankylosing spondylitis, psoriasis, Crohn's disease and type 2 diabetes.
The latest Crohn's research identified 21 new risk genes, bringing the total to more than 30 - though collectively they explain only about a fifth of the total genetic risk. This suggests that many additional genes contribute to Crohn's, and also illustrates how complex the condition is. The studies also picked up unexpected connections between diseases - one gene increases susceptibility to both Crohn’s and psoriasis, another contributes to both Crohn's and asthma.
As well as disease, genome-wide studies have also shed light on other biological characteristics, such as height. A further 20 genes affecting height were identified by an Anglo-Swiss consortium, bringing the total number to more than 100.
Particularly exciting has been the use of genome association studies in schizophrenia, which has been extremely hard to dissect genetically. A genome-wide analysis involving nearly 500 cases identified a number of potential genetic candidates, three of which were strongly confirmed in a follow-up in nearly 17 000 affected individuals.
Wellcome Trust-funded researchers also contributed to a major international collaboration looking for links between schizophrenia and copy number variation - deletion or duplication of small chunks of DNA. The presence of copy number variation was associated with an increased risk of schizophrenia, as was loss of specific sites on chromosomes 1 and 15.
The picture that is emerging is that variation at a great number of genes contributes to disease. Most are rare and most are non-deterministic - only a subset of people with a risk gene end up with the condition, possibly because of interactions with other risk genes or with environmental factors.
References
Capon F et al. Identification of ZNF313/RNF114 as a novel psoriasis susceptibility gene. Hum Mol Genet 2008;17(13):1938-45.
Fisher SA et al. Genetic determinants of ulcerative colitis include the ECM1 locus and five loci implicated in Crohn’s disease. Nat Genet 2008;40(6):710-2.
Weedon MN et al. Genome-wide association analysis identifies 20 loci that influence adult height. Nat Genet 2008;40(5):575-83.
Richards JB et al. Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study. Lancet 2008;371(9623):1505-12.
Barrett JC et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease. Nat Genet 2008;40(8):955-62.
O'Donovan MC et al. Identification of loci associated with schizophrenia by genome-wide association and follow-up. Nat Genet 2008;40(9):1053-5.
International Schizophrenia Consortium. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 2008;455(7210):237-41.
Ferreira MA et al. Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat Genet 2008;40(9):1056-8.
Sandhu MS et al. LDL-cholesterol concentrations: a genome-wide association study. Lancet 2008;371(9611):483-91.
Nejentsev S et al. Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A. Nature 2007;450(7171):887-92.
Wellcome Trust Case Control Consortium et al. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet 2007;39(11):1329-37.