Multifactorial Inheritance through the Eyes of Two Phenotypes: Hirschsprung Aganglionosis and Sudden Cardiac Death
The resolution of a multifactorial trait into its component genes remains as a classical yet difficult problem in human genetics. The understanding of human disease mechanisms has benefited greatly from the positional cloning of genes underlying Mendelian disorders. However, similar progress for the common complex diseases has been halting: are these disorders simply the agglomerative effects of their component gene effects?
I will discuss our experience in the molecular dissection of two contrasting complex phenotypes: the congenital birth defect Hirschsprung disease and an intermediate trait (QT-interval) associated with later-onset sudden cardiac death. Although both of these phenotypes have a fraction of cases displaying Mendelian inheritance, their requisite genes having been identified, the vast majority of cases are non-Mendelian. The primary features to emerge from our current knowledge is that: (1) only a few genes with significant effects can be identified implying that additional genes, if they exist, must individually contribute only a small amount to disease risk; (2) susceptibility alleles can be remarkably common and are suggestive of natural selection; (3) both coding and non-coding mutations can occur; (4) different susceptibility alleles can have markedly different effects on phenotype; and, (5) genetic interactions are critical. Our recent ability to map genetic variation at high density in individual genomes allows the identification of susceptibility alleles for complex disorders, and quantifying their properties, to remain a central and exciting human genetics endeavor.