ABSTRACT
Students in elementary genetics courses risk ending up supposing that Mendel’s patterns of inheritance describe the norm for how genes affect phenotypes. In addition to pointing out the impracticality of using model-free linkage to identify weak susceptibility factors, the Risch and Merikangas paper showed that, given certain assumptions, tests of association had much greater power. Yet it is clear that most susceptibility factors have even weaker effects than this. Almost always the combined effects of all known susceptibility factors identified through bottom-up studies account for less than half the heritability estimated from family studies. Identifying disease susceptibility factors can suggest novel leads for drug development, but the major benefit of genomic knowledge may be in selecting the most promising patients for clinical trials, and in predicting those at risk of adverse effects. Large-scale genome sequencing projects offer an alternative route to investigating the genetics of complex diseases.
