Biological complexity and strategies for finding DNA variations responsible for inter-individual variation in risk of a common chronic disease, coronary artery disease

Most common chronic diseases of humans aggregate, but do not segregate, in families. The segregation-linkage research paradigm has not provided great insights into their genetic etiology. In this paper, using coronary artery disease as an example, we discuss hierarchical organization, coherence, emergent properties and dynamism as features that characterize the complexity of genotype-phenotype relationships. We summarize a research strategy for evaluating the contribution of genetic and environmental factors to the prediction of inter-individual variation in risk of disease. We then review a statistical strategy that employs cladistic theory to identify individuals carrying mutant DNA sequences responsible for an observed association between marker variation in a gene and inter-individual variation in biological traits that determine risk of a common multifactorial disease. Finding these DNA sequences is a necessary step in our search for an understanding of the nature of the mapping of genetic variation into variation in risk of a disease like coronary artery disease.