Dataset Information

A second-generation genomic screen for multiple sclerosis.

ABSTRACT: Multiple sclerosis (MS) is a debilitating neuroimmunological and neurodegenerative disorder. Despite substantial evidence for polygenic inheritance of the disease, the major histocompatibility complex is the only region that clearly and consistently demonstrates linkage and association in MS studies. The goal of this study was to identify additional chromosomal regions that harbor susceptibility genes for MS. With a panel of 390 microsatellite markers genotyped in 245 U.S. and French multiplex families (456 affected relative pairs), this is the largest genomic screen for MS conducted to date. Four regions met both of our primary criteria for further interest (heterogeneity LOD [HLOD] and Z scores >2.0): 1q (HLOD=2.17; Z=3.38), 6p (HLOD=4.21; Z=2.26), 9q (HLOD; Z=2.71), and 16p (HLOD=2.64; Z=2.05). Two additional regions met only the Z score criterion: 3q (Z=2.39) and 5q (Z=2.17). Further examination of the data by country (United States vs. France) identified one additional region demonstrating suggestive linkage in the U.S. subset (18p [HLOD=2.39]) and two additional regions generating suggestive linkage in the French subset (1p [HLOD=2.08] and 22q [HLOD=2.06]). Examination of the data by human leukocyte antigen (HLA)-DR2 stratification identified four additional regions demonstrating suggestive linkage: 2q (HLOD=3.09 in the U.S. DR2- families), 6q (HLOD=3.10 in the French DR2- families), 13q (HLOD=2.32 in all DR2+ families and HLOD=2.17 in the U.S. DR2+ families), and 16q (HLOD=2.32 in all DR2+ families and HLOD=2.13 in the U.S. DR2+ families). These data suggest several regions that warrant further investigation in the search for MS susceptibility genes.

SUBMITTER: Kenealy SJ

PROVIDER: S-EPMC1182142 | biostudies-literature | 2004 Dec

REPOSITORIES: biostudies-literature

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A second-generation genomic screen for multiple sclerosis.

Kenealy S J SJ Babron M-C MC Bradford Y Y Schnetz-Boutaud N N Haines J L JL Rimmler J B JB Schmidt S S Pericak-Vance M A MA Barcellos L F LF Lincoln R R RR Oksenberg J R JR Hauser S L SL Clanet M M Brassat D D Edan G G Yaouanq J J Semana G G Cournu-Rebeix I I Lyon-Caen O O Fontaine B B

American journal of human genetics 20041019 6

Multiple sclerosis (MS) is a debilitating neuroimmunological and neurodegenerative disorder. Despite substantial evidence for polygenic inheritance of the disease, the major histocompatibility complex is the only region that clearly and consistently demonstrates linkage and association in MS studies. The goal of this study was to identify additional chromosomal regions that harbor susceptibility genes for MS. With a panel of 390 microsatellite markers genotyped in 245 U.S. and French multiplex f ...[more]

PMID: 15494893

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Project description:BACKGROUND:There are inconsistent reports about multiple sclerosis (MS) risk among migrants from low to high MS risk geographical regions. This study assessed the overall MS incidence and evaluated seasonality in birth and subsequent MS risk later in the life in second generation of migrants born and lived in Kuwait. METHODS:We assessed the overall and gender-specific MS risk in second generation of migrants born and lived in Kuwait between January 1, 1950 and April 30, 2013. Data on migrants' MS patients diagnosed and registered in Kuwait National MS Registry were used. Hewitt's non-parametric test was carried out to evaluate the seasonality in migrants' MS births in comparison with the second generation migrants' births in general population. RESULTS:During the study period, an overall risk of migrants' MS births (per 100,000 non-Kuwaiti births in general population) was 23.8 (95% CI: 20.8 - 27.0). Gender-specific MS risk showed that non-Kuwaiti female had statistically significant (p?=?0.003) higher risk (28.6; 95% CI: 24.2 - 33.7) than non-Kuwaiti males (18.7; 95% CI: 15.1-23.0). The month-specific distribution of migrants' MS births compared with migrants' births in general population did not differ significantly (?2 goodness-of-fit test statistic?=?9.51, p?=?0.575). Hewitt's non-parametric test revealed an evidence of slight but statistically non-significant (p?=?0.090) increased tendency of migrants' MS births during September through February. CONCLUSIONS:The proportion of migrants' MS births (per 100,000 migrants' births in general population) over the study period was 23.8 (95% CI: 20.8 - 27.0), which was statistically significantly higher than the previously reported Kuwaiti national MS births (16.2; 95% CI: 15.1-17.4) in Kuwait. Non-parametric analysis showed slight but statistically non-significant increased tendency of migrants' MS births from September through February. Knowledge of MS risk factors and how and when they act among genetically vulnerable individuals from gestation to early adulthood will help design prevention strategies.

Project description:Background: Multiple sclerosis (MS) is a complex disorder thought to result from an interaction between environmental and genetic predisposing factors which have not yet been characterised, although it is known to be associated with the HLA region on 6p21.32. Recently, a picture of chronic cerebrospinal venous insufficiency (CCSVI), consequent to stenosing venous malformation of the main extra-cranial outflow routes (VM), has been described in patients affected with MS, introducing an additional phenotype with possible pathogenic significance. Methods: In order to explore the presence of copy number variations (CNVs) within the HLA locus, a custom CGH array was designed to cover 7 Mb of the HLA locus region (6,899,999bp; chr6:29,900,001-36,800,000). Genomic DNA of the 15 patients with CCSVI/VM and MS was hybridised in duplicate. Results: In total, 322 CNVs, of which 225 were extragenic and 97 intragenic, were identified in 15 patients. 234 known polymorphic CNVs were detected, the majority of these being situated in non-coding or extragenic regions. The overall number of CNVs (both extra- and intragenic) showed a robust and significant correlation with the number of stenosing VMs (Spearman: r=0.6590, p=0.0104; linear regression analysis r=0.6577, p=0.0106). The region we analysed contains 211 known genes. By using pathway analysis focused on angiogenesis and venous development, MS, and immunity, we tentatively highlight several genes as possible susceptibility factor candidates involved in this peculiar phenotype. Conclusions: The CNVs contained in the HLA locus region in patients with the novel phenotype of CCSVI/VM and MS were mapped in detail, demonstrating a significant correlation between the number of known CNVs found in the HLA region and the number of CCSVI-VMs identified in patients. Pathway analysis revealed common routes of interaction of several of the genes involved in angiogenesis and immunity contained within this region. Despite the small sample size in this pilot study, it does suggest that the number of multiple polymorphic CNVs in the HLA locus deserves further study, owing to their possible involvement in susceptibility to this novel MS/VM plus phenotype, and perhaps even other types of the disease.

Dataset Information

A second-generation genomic screen for multiple sclerosis.

Publications

A second-generation genomic screen for multiple sclerosis.

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