The genetic aspects of multiple sclerosis

Abstract

THE EPIDEMIOLOGY OF MULTIPLE SCLEROSIS HAS BEEN EXTENSIVELY INVESTIGATED AND TWO FEATURES HAVE CONSISTENTLY EMERGED: marked geographical variation in prevalence and substantial familial clustering. At first sight, geographic variation would seem to imply an environmental cause for the disease, while familial clustering would seem to suggest that genetic factors have the predominant etiological effect. However, given that geographic variation in prevalence could result from variation in the frequency of genetic risk alleles and that familial clustering might result from shared environmental exposure rather than shared genetic risk alleles, it is clear that these crude inferences are unreliable. Epidemiologists have been resourceful in their attempts to resolve this apparent conflict between "nurture and nature" and have employed a whole variety of sophisticated methods to try and untangle the etiology of multiple sclerosis. The body of evidence that has emerged from these efforts has formed the foundation for decades of research seeking to identify relevant genes and this is the obvious place to start any consideration of the genetics of multiple sclerosis.

Keywords: Genetics; genome-wide association study; multiple sclerosis.

Figure 1

Global distribution of multiple sclerosis and migrations The five continents are depicted, showing areas of medium prevalence of multiple sclerosis (orange), areas of exceptionally high frequency (red), and areas with low rates (grey-blue). Some regions are largely uncharted so these colors are only intended to provide an impression of the geographical trends. Major routes of migration studied from high-risk zone of northern Europe are shown as dotted arrows. Studies involving migrants from low-risk to high-risk zones are shown as solid arrows. Reprinted from The Lancet, Vol. 372, Compston and Coles, Multiple sclerosis, 1502-1517, Copyright (2008), with permission from Elsevier.[2]

Figure 2

Recurrence risks for multiple sclerosis in families Age-adjusted recurrence risks for different relatives of probands with multiple sclerosis and the degree of genetic sharing between relatives and the proband. Pooled data from population-based surveys. Error bars indicate 95% confidence intervals. Reprinted from The Lancet, Vol. 372, Compston and Coles, Multiple sclerosis, 1502-1517, Copyright (2008), with permission from Elsevier.[2]

Figure 3

Posterior odds that a result is true, assuming risk alleles with a frequency of 10% and a genotype relative risk (GRR) of 1.2 and a multiplicative model This figure indicates the posterior odds that a result is true (plotted on a log scale on the y-axis) against the significance of the result (plotted as the negative log of the P-value on the x-axis). Five sample sizes are listed in the legend; in each, the number of cases and controls are equal. The 200 line thus indicates the posterior odds for a study involving 200 cases and 200 controls, and so on. Power was calculated using the online genetic power calculator.[92] Reprinted from Brain, Vol. 131, 3118-31, Copyright (2008), with permission from Oxford University Press.[63]

Figure 4

Expected P-value in follow-up studies of rs6897932, the IL7R-associated SNP The red line indicates the expected P-value and the dotted lines the 95% confidence intervals on this estimate (plotted as the negative log). It can thus be expected that 95% of the time the observed P-value will fall within this space. The horizontal dotted line indicates the nominal 5% significance level. Reprinted from Brain, Vol. 131, 3118-31, Copyright (2008), with permission from Oxford University Press.[63]