A putative vulnerability locus to multiple sclerosis maps to 5p14–p12 in a region syntenic to the murine locus Eae2

Kuokkanen, Satu; Sundvall, Mats; Terwilliger, Joseph D.; Tienari, Pentti J.; Wikström, Juhani; Holmdahl, Rikard; Pettersson, Ulf; Peltonen, Leena

doi:10.1038/ng0896-477

Cited by 190 publications

(99 citation statements)

References 24 publications

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“…These analyses were performed using the MLINK program of the LINKAGE package, 26 FASTLINK version 2.2. 27 Affected sib-pair analysis (ASP) was not primarily used as many of our families were extended, but to complement the NPL statistics the ASP analyses were performed using the SIBPAIR program 28 of the ANALYZE package. 29 Linkage disequilibrium was tested with a haplotype relative risk test as incorporated in the ANALYZE package.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide search in Finnish families with inflammatory bowel disease provides evidence for novel susceptibility loci

et al. 2003

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Epidemiological and genetic linkage studies have indicated a strong genetic basis for development of inflammatory bowel disease (IBD) which was recently supported by discovery of the Crohn's disease (CD) susceptibility gene termed NOD2/CARD15. We carried out a genome-wide linkage study in Finnish IBD families, providing a particular advantage to map susceptibility genes for ulcerative colitis (UC) within a genetic isolate. Initially, 92 IBD families with 138 affected sib-pairs (ASPs), were genotyped for 429 markers spaced at approximately 10 cM intervals. Next, the loci on chromosomes 2p13-11, 11p12-q13, and 12p13-12 were high-density mapped in the extended family cohort of 130 families with 173 ASPs. In this study, the most significant lod scores were observed for the UC families on chromosome 2p11 (D2S2333), in the vicinity of the REG gene cluster which is strikingly overexpressed in the IBD mucosa. The maximum two-point lod score was 3.34 (dominant model), and the corresponding NPL score 2.61. For UC, the second highest two-point NPL score of 2.00 was observed at proximal 12p13, where also some evidence for linkage disequilibrium emerged (P=0.07 and P=0.007 for the basic and extended IBD cohorts, respectively). The highest two-point NPL score for the CD families was 2.34 at D12S78 (12q23) with significant evidence for linkage disequilibrium (P=0.004), and for the mixed (MX) families 2.07 at D4S406 near the linkage peak reported previously. This study confirmed several of the IBD loci that have previously been reported and gives evidence for new IBD loci on chromosomes 2p11, 11p12-q13, 12p13-12, 12q23, and 19q13. European Journal of Human Genetics (2002) 11, 112 -120. doi:10.1038/sj.ejhg.5200936 Keywords: inflammatory bowel disease; genome-wide scan; genetic linkage Ulcerative colitis (UC) and Crohn's disease (CD) are chronic idiopathic, inflammatory disorders of the gastrointestinal tract, and are thought to arise from the interplay of genetic and environmental factors. Many features suggest a significant familial component to pathogenesis of these chronic inflammatory disorders. There is an increased risk among the first-degree relatives of IBD patients, with 5 -10% of the patients having an affected first degree-relative, and there is a higher concordance rate for monozygotic than dizygotic twins for the same disorder. 1 The concordance rate is two to three times higher in CD than in UC, suggesting that CD would be determined to a higher extent by genetic factors than UC. The assumption is, however, that CD and UC would also share at least some of the susceptibility genes, since many of the genetic loci are clearly contributed by both disorders and there are families segre-

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Section: Discussionmentioning

confidence: 99%

Genome-wide search in Finnish families with inflammatory bowel disease provides evidence for novel susceptibility loci

et al. 2003

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“…3 Most susceptibility loci, except perhaps the major histocompatibility complex, contribute only a small effect. [4][5][6][7][8] Association studies are powerful methods to uncover relatively small effects of allelic variants on complex traits. 9 Interferon-gamma (IFNg) stimulates Th-1 clonal expansion and inhibits Th-2 expansion.…”

Section: Introductionmentioning

confidence: 99%

IFNG polymorphisms are associated with gender differences in susceptibility to multiple sclerosis

et al. 2005

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Interferon-gamma (IFNg) treatment is deleterious in multiple sclerosis (MS). MS occurs twice as frequently in women as in men. IFNg expression varies by gender. We studied a population-based sample of US MS patients and ethnicity-matched controls and independent Northern Irish and Belgian hospital-based patients and controls for association with MS, stratified by gender, of an intron 1 microsatellite [I1 (761)

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“…Further illustration of the difficulty involved in determining the exact nature of MS inheritance is provided by the disappointing linkage results from affected relative pair studies (Ebers et al 1996;Haines et al 1996;Kuokkanen et al 1996;Sawcer et al 1996;Kuokkanen et al 1997;Oturai et al 1999;Broadley et al 2001;Coraddu et al 2001; Transatlantic Multiple Sclerosis Genetics Cooperative 2001; Akesson et al 2002;Ban et al 2002;Goedde et al 2002;Dyment et al 2004;Kenealy et al 2004). The major histocompatibility complex locus (MHC) has been consistently implicated as playing a role in MS inheritance.…”

Section: Introductionmentioning

confidence: 99%

A genome-wide scan in forty large pedigrees with multiple sclerosis

et al. 2007

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The epidemiology of multiple sclerosis suggests that a complex interaction of genes and environment contribute to susceptibility. To enrich for families with large genetic effects and to potentially reduce genetic heterogeneity, we screened a sample of 18,794 probands and identified forty families with four or more affected individuals. Within these 40 families, HLA DRB1*15 was present in 70% of affected individuals; the transmission disequilibrium test showed a significant excess in transmission of DRB1*15 alleles to affected individuals (47 transmitted, 19 untransmitted, v 2 = 11.9, p = 0.00057). A 10 cM genome scan was performed and analyzed for linkage under a parametric model with heterogeneity. No excess of significant sharing was observed (HLOD [ 3.3) in the parametric multipoint analysis. No region exceeded that for marker GATA8A05 with an HLOD = 1.11. Follow-up genotyping with 17 microsatellites revealed a significant two-point parametric HLOD = 3.99 at marker D4S1597. Transmission disequilibrium tests for markers in this candidate region showed no transmission distortion. A scan for variants in a gene adjacent to D4S1597, PALLD, was negative for synonymous or nonsynonymous changes. A final multipoint scan incorporating all microsatellites in the region provided an HLOD = 1.30. The inability to find significant linkage in these highly penetrant families suggests that linkage is not the optimal tool for dissecting the inheritance of MS.

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A putative vulnerability locus to multiple sclerosis maps to 5p14–p12 in a region syntenic to the murine locus Eae2

Cited by 190 publications

References 24 publications

Genome-wide search in Finnish families with inflammatory bowel disease provides evidence for novel susceptibility loci

Genome-wide search in Finnish families with inflammatory bowel disease provides evidence for novel susceptibility loci

IFNG polymorphisms are associated with gender differences in susceptibility to multiple sclerosis

A genome-wide scan in forty large pedigrees with multiple sclerosis

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