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This chapter is from the book

Three Reasons Why Genes Might Make Us Sick

The upshot of all this is that there are basically three ways that genetic variation can influence disease susceptibility. These are called the rare alleles, common variant, and small effect models. I will briefly describe each and then in the next section present a unified framework that iterates throughout the remaining chapters.

The simplest model is that a disease can be traced to one badly disrupted gene. This is pretty much the case for cystic fibrosis, and for thousands of other rare conditions. Around 1 in 100 of us carries a mutated version of the CFTR gene without any ill effects, but if two carriers marry, their children have a 1 in 4 chance of getting both bad copies and consequently having cystic fibrosis. The incidence in the general population is only about 1 in 10,000, most of which is due to a few mutations that have been around for centuries, but actually hundreds of other mutations can be found in the gene as well. Whether the disease is so severe that it claims the life of an infant, or mild enough that a person can live to adulthood and maybe receive a life-saving lung transplant, is in part a function of which mutations they have, in part of the rest of their genome, and in part their upbringing.

Single genes can also cause diseases in other ways. Muscular dystrophy is often due to a gene, dystrophin, that is so big that it picks up mutations often enough that most new cases arise in the individual who has the disease. Another small set of genes has an odd feature that makes them mutate at an unusually high rate, leading to the paralysis or ataxia observed in Fragile X syndrome and Huntington’s disease. For the most part, though, single gene diseases are rare.

Large-effect mutations also do not generally explain common diseases, those seen in five percent to ten percent or more of people. Really the only way they could is if there were hundreds of genes that cause a syndrome that we choose to think of as a single disease. Schizophrenia might be in this class, as might the wide spectrum of cardiovascular conditions that lead to heart attacks and stroke. It is possible that these rare mutations interact with one another, so that a person needs two or three of them in any condition to be predisposed to the disease. Unfortunately geneticists have not yet devised a systematic way to discover such mutations.

Currently the most popular model is called the common disease-common variant, or CD-CV, hypothesis. It is the idea that if there are diseases found in ten percent of the population, then there ought to be alleles at about the same frequency that are found in these people, but not in “normal” people. This sounds reasonable enough, so millions and millions of dollars are being spent in pursuit of these alleles, each of which contributes about five percent to ten percent of the risk of illness. So far, Crohn’s disease, an inflammatory bowel syndrome, is the poster child success story, except that it is not actually a common disease. However, ten or so genes have been discovered that contribute to Crohn’s, each with correspondingly common risk alleles. Diabetes and prostate cancer also show signs of following the CD-CV model, but the jury is out on whether this will really be a common explanation for disease.

The third possibility is that hundreds if not thousands of different genes—each with rare or common alleles that have small, barely detectable effects—contribute to each common disease. To some extent this is the default model when all other models fail, but it is beginning to look like it is going to be the predominant explanation. The trouble is that this model doesn’t really explain why diseases are discrete. Height, degree of extraversion, memory performance, and probably most human attributes are thought to be influenced by hundreds of genes, but they show a continuous gradation from short to tall, shy to outrageous, and forgetful to prolific. So why should there be people with disease and people without disease, if hundreds of genes are involved?

A somewhat technical explanation for this is that there is a threshold of liability—in other words, a tipping point from health to sickness whenever you have a little more of something than is normally tolerated. Most people are pretty similar genetically, having average levels of whatever it is. They have some genes that increase the attribute and some that decrease it, but generally not an excess of either. However, inevitably a few outliers will have considerably more of the increasing or decreasing alleles, enough to send them beyond the threshold into the valley of illness.

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