Erratum: Genome-wide association identifies multiple ulcerative colitis susceptibility loci.
- SourceAvailable from: PubMed Central[Show abstract] [Hide abstract]
ABSTRACT: Genetic studies have identified more than 150 autoimmune loci, and next-generation sequencing will identify more. Is it time to make human the model organism for autoimmune research?Genome biology 05/2010; 11(5):212. DOI:10.1186/gb-2010-11-5-212 · 10.47 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Discoveries from genome-wide association studies have contributed to our knowledge of the genetic etiology of many complex diseases. However, these account for only a small fraction of each disease's heritability. Here, we comment on approaches currently available to uncover more of the genetic 'dark matter,' including an approach introduced recently by Naukkarinen and colleagues. These authors propose a method for distinguishing between gene expression driven by genetic variation and that driven by non-genetic factors. This dichotomy allows investigators to focus statistical tests and further molecular analyses on a smaller set of genes, thereby discovering new genetic variation affecting risk for disease. We need more methods like this one if we are to shed a powerful light on dark matter. By enhancing our understanding of molecular genetic etiology, such methods will help us to understand disease processes better and will advance the promise of personalized medicine.Genome Medicine 10/2010; 2(10):79. DOI:10.1186/gm200 · 4.94 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Several susceptibility genetic variants for autoimmune diseases have been identified. A subset of these polymorphisms displays an opposite risk profile in different autoimmune conditions. This observation open interesting questions on the evolutionary forces shaping the frequency of these alleles in human populations.We aimed at testing the hypothesis whereby balancing selection has shaped the frequency of opposite risk alleles. Since balancing selection signatures are expected to extend over short genomic portions, we focused our analyses on 11 regions carrying putative functional polymorphisms that may represent the disease variants (and the selection targets). No exceptional nucleotide diversity was observed for ZSCAN23, HLA-DMB, VARS2, PTPN22, BAT3, C6orf47, and IL10; summary statistics were consistent with evolutionary neutrality for these gene regions. Conversely, CDSN/PSORS1C1, TRIM10/TRIM40, BTNL2, and TAP2 showed extremely high nucleotide diversity and most tests rejected neutrality, suggesting the action of balancing selection. For TAP2 and BTNL2 these signatures are not secondary to linkage disequilibrium with HLA class II genes. Nonetheless, with the exception of variants in TRIM40 and CDSN, our data suggest that opposite risk SNPs are not selection targets but rather have accumulated as neutral variants. Data herein indicate that balancing selection is common within the extended MHC region and involves several non-HLA loci. Yet, the evolutionary history of most SNPs with an opposite effect for autoimmune diseases is consistent with evolutionary neutrality. We suggest that variants with an opposite effect on autoimmune diseases should not be considered a distinct class of disease alleles from the evolutionary perspective and, in a few cases, the opposite effect on distinct diseases may derive from complex haplotype structures in regions with high genetic diversity.BMC Evolutionary Biology 06/2011; 11:171. DOI:10.1186/1471-2148-11-171 · 3.41 Impact Factor