Quote: Lederberg on the candidate gene approach

In my last post (“Quote: Lederberg on Haldane”) I pointed to a 1999 article by Joshua Lederberg Lederberg:Haldane:1999. Later in the article, he considers an interesting question:

Outside the domain of malaria and the erythrocyte, the pickings for established polymorphisms in relation to human disease are rather thin. Why have they predominated for malaria? Its geographic, climatic, and altitudinal restrictionsrelated to the habitats of vector mosquitoeslend themselves to epidemiological revelation. In addition, few diseases, barring mainly tuberculosis, have a prevalence and fitness-impairing morbidity so high that subject genes will have significant penetrance. Most other morbid infections will attack a small sector of the population, thus introducing high environmental variance into the heritability calculations. This is also compounded by maternally inherited immunity and, needless to say, elements of culture (including saluto-genic technology). Most of our successes have entailed the ascertainment of candidate genes, e.g., the blood group and MHC polymorphisms, and searches for disease correlations to them. These are abundant and can be partially explained by specializations in epitope presentation to the immune system or antigenic mimicry between parasites' surface antigens and self-antigens of the host.

Today we have GWAS, which has potentially much greater power to show associations between large samples of people and previously unknown risk loci. Yet the same limitations remain true that Lederberg pointed out in 1999: Environmental variance in parasite or pathogen incidence and load is very high, acquired immunity complicates the analysis of effects, and the present effects of pathogens are different than they would have been in past populations with greater frailty.