Formal genetics of humans: Multifactorial inheritance and common diseases

Abstract

The study of the genetics of complex traits is made complicated by the fact that the traits themselves are influenced by an interplay of many genes with many environmental factors. In this chapter the historical concepts of quantitative genetics, including additive variance and heritability, will be developed to underscore how important it is to understand that the root of the problem is to explain how genes contribute to the variance in a trait. With molecular genetic markers, such as SNPs, it is possible to test whether there are differences in the measured phenotype among the genotypes at the genetic marker, and this serves as a crude test of association. Many interesting challenges arise when such a test is expanded to 1 million markers spanning the entire chromosome, a design known as a genome-wide association study (GWAS). Complications due to population stratification, admixture, genotype x environment interaction, epistasis, and rare alleles are all considered. Methods that test association by use of excess of allele sharing in siblings (affected sib methods) or other relatives, or by excess cotransmission of alleles and a disease state (transmission disequilibrium test) have their own set of advantages and disadvantages. The chapter closes with some considerations of why the powerful methods presented here nevertheless leave much of the genetic variance in complex traits unexplained.