Susceptibility Linkage

It has long been recognized that, despite living at geographical latitudes where multiple sclerosis (MS) is common, genetically isolated ethnic groups—including Gypsies in Hungary (1); Indians and Orientals in North America (2); Aborigines in Australia (3); and Maoris in New Zealand (4)—remain resistant to the disease. Systematic analysis of familial aggregation of MS—in particular, studies of twins (5-8), adoptees (9), and half-siblings (10)—has also confirmed Eichhorst's description from the 1890s of MS as a "heritable" disorder (11). The degree to which a disease is heritable can be estimated by dividing the lifetime risk of siblings to affected individuals by the population prevalence of the disease, to yield the so-called ks statistic. For MS, in high-risk populations, ks is between 20 (0.02/0.001) and 40 (0.04/0.001)—a value similar to that seen in insulin-dependent diabetes mellitus (12). Data from twin studies—which show that the concordance rate of approximately 30% in monozygotic twins drops steeply to a rate below 5% for dizygotic twins—strongly indicate that susceptibility to MS is influenced by many genes in combination (13).

To date, studies conducted with the goal of identifying susceptibility-conferring genes in MS have for the most part taken the form of either linkage screens, in which the segregation of polymorphic microsatellite markers, located throughout the entire genome or at candidate loci, is analyzed in collections of multicase MS families, or association studies, in which genotype frequencies at polymorphic positions in or near selected genes are compared in sporadic MS cases and ethnically matched healthy controls. In 1996, the results of three large multi-stage genome-wide screens performed on datasets of affected relative pairs collected in the United Kingdom (14), the United States and France (15), and Canada (16) were published; results from a fourth Finnish screen (17) appeared the following year. Each screen uncovered multiple loci of potential involvement in MS, supporting genetic-epidemiological suggestions of polygenic inheritance. A number of loci—including the HLA region on chromosome 6p21—were positive for linkage in more than one study.

In 2001, a meta-analysis was performed on the raw genotyping data from the British, Franco-American, and Canadian screens (18). Eight chromosomal regions displayed nonparametric linkage (NPL) scores greater than 2.0: 17q11, 6p21, 5q11, 17q22, 16p13, 3p21,12p13, and 6qtel (in descending order). For no region, however, did NPL scores reach levels indicative of genome-wide significance. The authors offered two alternative explanations for the "failure" of their meta-analysis: ''The first is that genetic factors with substantial effects do not exist and susceptibility to the disease is more likely determined by many genes, each exerting a relatively modest effect, acting together. The other possibility is that genes with large effects do exist in some families, but because of the genetic complexity of MS, these genes cannot be defined in a heterogeneous outbred population.''

Since the publication of that meta-analysis, five additional genome-wide linkage screens have been performed on MS families from mainland Italy (19), Sardinia (20), the Nordic countries (21), Australia (22), and Turkey (23). In addition, as part of the Genetic Analysis of Multiple Sclerosis in Europeans (GAMES) project discussed below, a renewed meta-analysis was performed (24), which incorporated data from all nine genome screens (Table 1). Although the number of non-HLA regions exhibiting NPL scores greater than 2.0 had now been narrowed down from seven to four—11ptel, 16p13, 17q21, and 22q13—only one region exceeded the threshold for genome-wide statistical significance: HLA on 6p21.

Table 1 Regions Displaying Positive Linkage in Nine Genome-Wide Linkage Screens of Multicase Multiple Sclerosis Families and One Meta-Analysis of These Screens

Note: U, United Kingdom, (14), maximum LOD score (MLS) > 1.8; Am, United States and France, (15), positive in at least two-thirds of tests; C, Canada, (16), 56% sharing; F, Finland, (17), nonparametric linkage (NPL) > 1.0; I, Italy, (19), LOD > 0.7; S, Sardinia, (20), MLS > 1.8; N, Nordic countries, (21), LOD > 0.7; A, Australia, (22), MLS > 0.7; T, Turkey, (23), MLS > 1.8; M, meta-analysis, (24), NPL > 2.0.

Source: From Ref. 25.

Chr1

Chr2

Chr3

Chr4

Chr5

Chr6

Chr7

Chr8

Chr9

Chr10

Chr11

Chr12

Chr13

Chr14

Chr15

Chr16

Chr17

Chr18

Chr19

Chr20

Chr21

Chr22

ChrX

p35(C), p21(U), q11-24(N), q31(S), q42-44(l,A) p23(Am), p21(C), p13(A), q24-33(G,F,N), q36(l) p26(N), p25(C), p14(C), q21-24(Am,C,F,N,A), q26(C) p16(C), q12(F,N), q24(A), q26-28(C,A), q31-35(Am,A) ptel-14(C), p14-12(F), q11-13(U,A), q13-23(Am,C), q33(l) p25(I,N), p21(Am,F,N,M), q14(C), q21(N), q22(l), q26(A), q27(A) p21(C), p15(U), p14(C), q11(Am), q21-22(Am,C), q32-35(Am,A) p23-21(A)

p15(N), p13-12(N), cen(l), q21-22(Am,F), q24(S), q26(C)

p13(Am,N,A,M), p11(A), q12(C), q23-24(A) p13(A), q21(M), q22-24(U,F), q25(N) p11(Am,C,F,A), q21(C), q23(T) q13(Am,C,F) p12(A)

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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