The Genetics of Common Diseases: 10 Million Times as Hard

The transition taking place in human genetics could notbe more pronounced. Over the past 20 odd years, humangeneticists have identified more than 1200 genes causingMendelian diseases, and with few exceptions, the identifications have been unambiguous and uncontroversial.On the other hand, we know next to nothing about the genetics of common diseases that are influenced by multiple genes in a complicated interaction with the environment. There are only about 20 different polymorphismsthat are generally accepted as risk factors for theseso-called "complex" diseases (Glazier et al. 2002;Hirschhorn et al. 2002; Botstein and Risch 2003). It is notonly in the disparity between the remarkable successes inthe Mendelian cases, and the striking failure in the case ofcommon diseases, that the contrast is apparent. It is alsoin the cultures of the two research enterprises. When anew Mendelian mutation is identified, the evidence usually requires little qualification: The mutation is found inmultiple affected members of a pedigree, it is never observed in unaffected individuals, and it knocks out or alters the properties of an important and relevant protein,and so on. There is no follow-up flood of publications debating whether or not it is really the disease gene. Whenresults on common diseases are presented, it is not uncommon for researchers to say that "this associationlooks biologically plausible so I tend to believe it." A literature debate invariably ensues...