In keeping with the DNA metaphor, the idea of the genomic approach is to assume that genes simply must be causing a trait of interest, and to look across the entire genome to find variants that are more common in individuals with the trait than in those without it. The hope was that we would soon eliminate the debilitating or fatal diseases to which most of us now fall victim, once we had exhaustive knowledge of genome-wide variation.
Genomic studies searching for causal genes have grown ever larger and more expensive, but commensurately important results have yet to roll in. Most of the estimated overall genetic influence on the traits or diseases of interest is still unidentified. What we’re finding instead is ‘polygenic’ causation, that is, that many different parts of the genome contribute mainly trivial individual effects.
A typical well-studied example is Crohn’s disease, an inflammatory bowel disease that runs in families, and thus would seem to have a major genetic component. However, the most recent study, by Heather Elding and colleagues at University College London, published in The American Journal of Human Genetics, estimates that the number of genes associated with the disease is around 200, most with very small effects, which explains only a small amount of the genetic background of this disease. To liken this again to coin-flipping, variants at each ‘causal’ gene affect risk in some probabilistic way, usually very small — far from 50-50 — and with no guarantee whatever that the same variant provides the same risk in different people who carry it, or in different populations, or in men or women, or at different ages. It’s as though each coin keeps changing its probability of coming up heads. Thus, the predictive power of this type of ‘personalised genomic medicine’ is generally very weak, like trying to predict the outcome of hundreds of individual-specific coin-flips. That’s why, with some fortunate exceptions, the clinical or therapeutic value of all these genetic studies has so far been slight.
