The Future of Genetic Studies of Complex Human Diseases

Abstract

With advances in the human genome project and the increasing availability of deoxyribonucleic acid (DNA) markers scattered throughout the genome, such as simple sequence polymorphisms, variable number tandem repeats, and short sequence repeat polymorphisms, it has become increasingly possible to search for the genetic basis of complex human diseases using genome-wide screening methods.1-3 Linkage analysis using log odds (LOD) score analysis in large pedigrees has been the traditional tool to identify gene loci for human disorders, both for single-gene disorders (for example, Huntington's disease4) and for complex chronic diseases (such as bipolar disease5). Recently, Risch and Merikangas6 have argued that the future of genetic studies of complex human disease may depend, to a large extent, on applications of new association-type methods to familybased data.7 The main method of interest is the trans? mission disequilibrium test (TDT), in which alleles at a given locus for a person with a specific disease are compared with parental nontransmitted alleles to look for evidence of deviation from expectations in the ab? sence of linkage.8 The TDT has been shown to be a valid test of linkage in the presence of linkage disequilibrium (which creates associations with specific alleles). They showed that the TDT has more power than traditional linkage analysis for disease genes with weak to moderate effects on disease risks. In this paper, we argue that the future of the genetic study of complex disorders will rely increasingly on the classical epidemiologic association paradigm. We show that in the long run, improvements in study designs and in adjusting for population stratification using interviews and genetic markers will lead to a new era of populationbased incident case-control studies that could have more power, can lead to more detailed information on the presence or absence of a disease susceptibility gene, and define the magnitude of risks and gene-environment interaction, a crucial first step to disease prevention and health promotion.