RESUMEN
By combining all the data available from the Genetic Analysis of Multiple sclerosis in EuropeanS (GAMES) project, we have been able to identify 17 microsatellite markers showing consistent evidence for apparent association. As might be expected five of these markers map within the Major Histocompatibility Complex (MHC) and are in LD with HLA-DRB1. Individual genotyping of the 12 non-MHC markers confirmed association for three of them--D11S1986, D19S552 and D20S894. Association mapping across the candidate genes implicated by these markers in 937 UK trio families revealed modestly associated haplotypes in JAG1 (p=0.019) on chromosome 20p12.2 and POU2AF1 (p=0.003) on chromosome 11q23.1.
Asunto(s)
Proteínas de Unión al Calcio/genética , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Péptidos y Proteínas de Señalización Intercelular/genética , Desequilibrio de Ligamiento/genética , Proteínas de la Membrana/genética , Esclerosis Múltiple/genética , Transactivadores/genética , Europa (Continente)/epidemiología , Femenino , Genotipo , Humanos , Proteína Jagged-1 , Masculino , Repeticiones de Microsatélite , Esclerosis Múltiple/epidemiología , Proteínas Serrate-JaggedRESUMEN
Genome-wide screens for linkage in multiplex families with multiple sclerosis (MS) from United Kingdom, Sardinia, Italy and the Nordic countries (Denmark, Finland, Norway and Sweden) have each shown suggestive or potential linkage on chromosome 10. The partially overlapping regions identified by these studies encompass around 60 cM of the chromosome. In order to explore this region further, we typed 13 microsatellite markers in the same 449 families originally studied in the individual screens. This additional genotyping increased the information extraction in the region from 52% to 79% and revealed increased support for linkage (MLS 2.5) peaking at 10p15.
Asunto(s)
Cromosomas Humanos Par 10/genética , Ligamiento Genético , Esclerosis Múltiple/genética , Hermanos , Alelos , Finlandia/epidemiología , Pruebas Genéticas/métodos , Genotipo , Humanos , Cooperación Internacional , Italia/epidemiología , Repeticiones de Microsatélite/genética , Esclerosis Múltiple/epidemiología , Países Escandinavos y Nórdicos/epidemiología , Programas InformáticosRESUMEN
Using indirect whole genome association screening, we have searched for multiple sclerosis susceptibility genes in the genetically isolated high risk Sardinian population. Two screens were performed; the first was based on 229 cases and 264 unrelated controls, and the second on 235 trio families. Each screen employed a dense set of microsatellite markers and DNA pooling. Data from both screens were available from 2764 markers. Nine markers showed nominally significant results in both screens independently. Five of these markers-D2S408 (2q36), D6S271 (6p21), D6S344 (6p25), D7S1818 (7p12) and D16S420 (16p12)-remained nominally significant in both studies after conservative refining analysis.
Asunto(s)
Pruebas Genéticas , Genoma Humano , Desequilibrio de Ligamiento/genética , Esclerosis Múltiple/genética , Adulto , Alelos , Estudios de Casos y Controles , Reacciones Falso Positivas , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Pruebas Genéticas/métodos , Pruebas Genéticas/estadística & datos numéricos , Genética de Población , Genotipo , Humanos , Cooperación Internacional , Italia/epidemiología , Repeticiones de Microsatélite , Esclerosis Múltiple/epidemiologíaRESUMEN
Linkage analysis in multiplex families has provisionally identified several genomic regions where genes influencing susceptibility to multiple sclerosis are likely to be located. It is anticipated that association mapping will provide a higher degree of resolution, but this more powerful approach is limited by the substantial genotyping effort required. Here, we describe the first use of DNA pooling to screen the whole genome for association in multiple sclerosis based on a 0.5 cM map of microsatellite markers and using four DNA pools derived from cases (n = 216), controls (n = 219) and trio families (n = 745 affected individuals and their 1490 parents). The 10 markers showing the greatest evidence for association with multiple sclerosis that emerge from this analysis include three from the HLA region on chromosome 6p (D6S1615, D6S2444 and TNFa), providing a positive control for the method, four from regions previously identified by linkage analysis in UK multiplex families (two mapping to chromosome 17q GCT6E11 and D17S1535; one to chromosome 1p GGAA30B06; and one to 19q D19S585), and three from novel sites with respect to linkage analysis (D1S1590 at 1q; D2S2739 at 2p; and D4S416 at 4q). Our results thus provide further supporting evidence for the candidature of 6p, 17q, 19q and 1p as regions encoding susceptibililty genes for multiple sclerosis. The protocol used in this UK-based study is now being extended to 18 additional sites in Europe in order to search for susceptibility genes shared between populations of common ancestry, as well as those that exert ethnically more restricted effects.