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Multiple Enhancer Variant Hypothesis for Susceptibility to Common Disease

Many rare disorders, like sickle cell anemia, are caused by gene mutation. Yet, until now, the underlying genetic cause of more common conditions – for example, rheumatoid arthritis – has eluded scientists for years. New research from Case Western Reserve University School of Medicine finds that six common diseases arise from DNA changes located outside genes. The study from the laboratory of Peter Scacheri, Ph.D., shows that multiple DNA changes, or variants, work in concert to affect genes, leading to autoimmune diseases including rheumatoid arthritis. Further, for each disease, multiple different genes are manipulated by several small differences in DNA. The study is entitled, “Combinatorial Effects of Multiple Enhancer Variants in Linkage Disequilibrium Dictate Levels of Gene Expression to Confer Susceptibility to Common Traits.” In the study, the authors present evidence that for six common autoimmune disorders (rheumatoid arthritis, Crohn’s disease, celiac disease, multiple sclerosis, lupus, and ulcerative colitis) genome-wide associations arise from multiple polymorphisms in linkage disequilibrium that map to clusters of enhancer elements active in the same cell type. The authors say that this finding suggests a “multiple enhancer variant” hypothesis for common traits, whereby several variants in linkage disequilibrium impact multiple enhancers and cooperatively affect gene expression. They go on to show that multiple enhancer variants within a given locus typically target the same gene. The authors conclude that the “multiple enhancer variant” hypothesis offers a new paradigm by which non-coding variants can confer susceptibility to common traits. The research was published online on November 6, 2013 in Genome Research. The Scacheri lab's study provides a new model for understanding how genetic variants explain variation in common, complex diseases such as rheumatoid arthritis and colitis--that is, the effect of an individual variant may be very small, but when coupled with other nearby variants, the manifestations are much greater, said Anthony Wynshaw-Boris, M.D., Ph.D., chair of the Department of Genetics and Genome Sciences at Case Western Reserve University School of Medicine and University Hospitals Case Medical Center and the James H. Jewell MD '34 Professor of Genetics at the School of Medicine. “This model may also help to explain why genetic studies of these and other common diseases have so far fallen short of providing a satisfactory explanation of the genetic pathways important for the development of these disorders." [Press release] [Genome Research abstract]