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Titolo:
THE GENETICS OF MULTIPLE-SCLEROSIS - PRINCIPLES, BACKGROUND AND UPDATED RESULTS OF THE UNITED-KINGDOM SYSTEMATIC GENOME SCREEN
Autore:
CHATAWAY J; FEAKES R; CORADDU F; GRAY J; DEANS J; FRASER M; ROBERTSON N; BROADLEY S; JONES H; CLAYTON D; GOODFELLOW P; SAWCER S; COMPSTON A;
Indirizzi:
UNIV CAMBRIDGE,ADDENBROOKES HOSP,NEUROL UNIT,HILLS RD CAMBRIDGE CB2 2QQ ENGLAND UNIV CAMBRIDGE,ADDENBROOKES HOSP,NEUROL UNIT CAMBRIDGE CB2 2QQ ENGLAND UNIV FORVIE SITE,INST PUBL HLTH,MRC,BIOSTAT UNIT CAMBRIDGE ENGLAND UNIV CAMBRIDGE,DEPT GENET CAMBRIDGE CB2 3EH ENGLAND UNIV FORVIE SITE,MRC,CAMBRIDGE CTR BRAIN REPAIR CAMBRIDGE ENGLAND
Titolo Testata:
Brain (Print)
, volume: 121, anno: 1998,
parte:, 10
pagine: 1869 - 1887
SICI:
0006-8950(1998)121:<1869:TGOM-P>2.0.ZU;2-I
Fonte:
ISI
Lingua:
ENG
Soggetto:
BASIC-PROTEIN GENE; CHAIN VARIABLE REGION; MAJOR SUSCEPTIBILITY LOCUS; BIPOLAR AFFECTIVE-DISORDER; SIB-PAIR ANALYSIS; PRIMERS PCR-SSP; WIDE SEARCH; SIBLING PAIRS; NO LINKAGE; POLYMORPHISMS;
Keywords:
MULTIPLE SCLEROSIS; SUSCEPTIBILITY GENES; MAJOR HISTOCOMPATIBILITY COMPLEX; GENOME SCREEN;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
96
Recensione:
Indirizzi per estratti:
Citazione:
J. Chataway et al., "THE GENETICS OF MULTIPLE-SCLEROSIS - PRINCIPLES, BACKGROUND AND UPDATED RESULTS OF THE UNITED-KINGDOM SYSTEMATIC GENOME SCREEN", Brain (Print), 121, 1998, pp. 1869-1887

Abstract

Genetic susceptibility to multiple sclerosis is implicated on the basis of classical family studies and phenotype analyses. The only reproducible legacy from the candidate gene approach has been the discovery of population associations with alleles of the major histocompatibility complex; Systematic genome scanning has since been applied using a panel of anonymous markers to identify areas of linkage in co-affected siblings. Here, we describe the principles of genome screening and update the UK survey of multiple sclerosis. This identified 20 regions ofpotential interest, but in none was there unequivocal linkage. In theory, attempting to replicate these findings in a second set of siblingpair families is the most appropriate way to distinguish true from false positives, but unfortunately the number of families required to dothis reliably is prohibitively large. We used three approaches to increase the definition achieved by the screen: (i) the number of siblingpairs typed in an identified region of potential linkage was extended; (ii) the information extraction was increased in an identified region; and (iii) a search was made for missed regions of potential linkage. Each of these approaches has considerable limitations. A chromosome-by-chromosome account is given to direct future searches. Although an additional marker placed distal to the 'hit' on chromosome 14q increased linkage in this area, and typing extra sibling pairs increased linkage on chromosomes 6p and 17q, evidence for linkage was more commonly reduced and no additional regions of interest were found. A further refinement of the genome screen was undertaken by conditioning for the presence of HLA-DR15. This produced a surprising degree of segregation among the regions of interest, which divided into two distinct groups depending on DR15 sharing: the DR15-sharing cohort comprised loci on chromosomal areas Ip, 17q and X; and the DR15-non-sharing cohort was made up of loci on 1cen, 3p, 7p, 14q and 22q. This result further highlights the genetic complexity of multiple sclerosis. What can now be inferred is that a gene of major effect is excluded from 95% of the genome and one with a moderate role from 65%, whereas genes which make a very small biological contribution cannot be discounted from any region. The available results suggest that multiple sclerosis depends on independent or epistatic effects of several genes each with small individual effects, rather than a very few genes of major biological importance.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 05/04/20 alle ore 06:54:30