Genetic susceptibility to infectious diseases: big is beautiful, but will bigger be even better?

Abstract

Genetic epidemiology, including twin studies, provides robust evidence that genetic variation in human populations contributes to susceptibility to infectious disease. One of the major limitations of studies that attempt to identify the genes and mechanisms that underlie this susceptibility has been lack of power caused by small sample size. With the development of novel technologies, burgeoning information on the human genome, the HapMap project, and human genetic diversity, we are at the beginning of a new era in the study of the genetics of complex diseases. This review looks afresh at the epidemiological evidence that supports a role for genetics in susceptibility to infectious disease, examines the somewhat limited achievements to date, and discusses current advances in methodology and technology that will potentially lead to translational data in the future.

Figure

Power to detect allelic association for a risk allele having an effect size (odds ratio) of 1·5 (A) 500, (B) 1500, and (C) 3000 trios or case-control pairs. Power is calculated for different frequencies of risk alleles, and for samples of 500, 1500, or 3000 trios or case-control pairs. Power approximations for trios by a standard transmission disequilibrium test have been made using the method of Knapp. Theoretical power to detect allelic association was made assuming a multiplicative model. Results are given as a first approximation of the percentage power to detect allelic association at p=0·01, p=0·001, or p=0·0001. Power calculations were essentially identical for a similar size case-control sample. The advantage of trios is that they are not influenced by population admixture. The advantage of case-control analysis is one third less genotyping to obtain equivalent power. The graphs show that 500 trios or case-control pairs have very poor power to detect allelic association even for relatively common risk alleles (frequencies >0·2). A sample of 1500 trios or case-control pairs has good power for risk alleles at frequencies >0·1. A sample of 3000 trios or case-control pairs improves power for rare risk alleles (frequencies <0·1).