On Sequence Variants that Influence the Risk of Common Diseases

Abstract

Sequence variants impacting risk of common diseases have the following characteristics: Most of the risk of common diseases is conferred by common variants of modest effect although there are rare variants of large effect that account for a small minority of cases. The risk variants are rarely in coding sequences. They generally influence expression of genes and in that determine where on the spectrum of physiologic function an individual falls. The risk variants are common because they have been under selection and carried with them advantage at some point in time or other alleles at their loci have conferred disadvantage.

Keywords: selection; genome‐wide association; genetics; common diseases; diabetes; myocardial infarction

Figure 1.

The figure shows a cartoon of the 5‐leukotriene synthetic pathway. Variants in the genes encoding FLAP and LTA4H conferring risk of heart attack are both associated with increased production of LTB4 (Helgadottir et al., ). Hence, it appears that both variants confer increase in the risk of heart attack by upregulating the leukotriene pathway. One way to contain the risk may be by turning down the pathway pharmacologically.

Figure 2.

The figure shows a hypothetical graph where each point on the graph represents a sequence variant influencing the expression of a disease gene. The farther away from the centre of the x‐axis, the greater the effect of the variant and the less is its frequency. Our hypothesis is that the genetics of common/complex traits is often the same as the genetics of gene expression and that individuals at one end of the spectrum of expression are at a greater than average risk and those at the other end are at a lesser than average risk. Where on the spectrum of expression the individual falls decides where on the spectrum of physiologic function he falls. This hypothesis is supported by data coming from many sources including those showing that there may be several sequence variants over the same gene each conferring distinct risk of or protection against a disease.

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Further Reading

Plenge RM, Cotsapas C, Davies L et al. (2007) Two independent alleles at 6q23 associated with risk of rheumatoid arthritis. Nature Genetics 39: 1477–1482.

Sabeti PC, Varilly P, Fry B et al. (2007) Genome‐wide detection and characterization of positive selection in human populations. Nature 449: 913–918.

Thomson W, Barton A, Ke X et al. (2007) Rheumatoid arthritis association at 6q23. Nature Genetics 39: 1431–1433.

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Stefánsson, Kári, and Gulcher, Jeffrey R(Jul 2008) On Sequence Variants that Influence the Risk of Common Diseases. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0020817]