The genetics of autoimmunity

Positional cloning of genes underlying the heritability of autoimmune disease, as in many complex diseases, has largely been a frustrating exercise with few replicated positive ¢ndings despite enormous e¡orts at linkage and association mapping over the past ten years. Similar di⁄culties have been encountered by researchers attempting to identify such genes in murine models of autoimmunity. One reason is the lack of primary knowledge of genetic variation patterns that would enable the more e⁄cient design and interpretation of comprehensive genetic association studies. We here describe progress towards haplotype maps of both the human and mouse genomes including their current application in the search for genes underlying autoimmune and in£ammatory disorders. 2005 The genetics of autoimmunity. Wiley, Chichester (Novartis Foundation Symposium 267) p 2^13 The promise and excitement surrounding human genetics lies in the opportunity to discover the fundamental basis of heritable disease and in the potential longterm impact on treatment of disease that lies beyond such discoveries. While this dream of personalized medicine and rational therapeutic development was one of the driving forces behind the recently completed Human Genome Project, such goals have largely been elusive, particularly for autoimmune and other common, complex diseases. One of the main obstacles towards realizing some of these future bene¢ts has been the di⁄culty in identifying the genetic factors underlying risk, severity and therapeutic response seen as a critical ¢rst step towards the improved biological understanding and diagnostic classi¢cation that is required to accelerate progress towards better treatment and prevention. By contrast, enormous success has been achieved in the identi¢cation of genes and mutations underlying monogenic (Mendelian) disorders with more than 1000 successful e¡orts to date (Botstein & Risch 2003). In Mendelian disorders, the presumption of monogenicity and complete penetrance of the mutations has enabled the rapid identi¢cation of small disease intervals because a¡ected relative pairs must share these necessary and su⁄cient mutations. In this scenario, single