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Stephen Sawcer,
Garrett Hellenthal,
Matti Pirinen,
Chris C A Spencer,
Nikolaos A Patsopoulos,
Loukas Moutsianas,
Alexander Dilthey,
Zhan Su,
Colin Freeman,
Sarah E Hunt, [......],
Jan Hillert,
Adrian J Ivinson,
Philip L De Jager,
Leena Peltonen,
Graeme J Stewart,
David A Hafler,
Stephen L Hauser,
Gil McVean,
Peter Donnelly,
Alastair Compston
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ABSTRACT: Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
Nature 08/2011; 476(7359):214-9. · 36.28 Impact Factor
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Eveliina Jakkula,
Virpi Leppä,
Anna-Maija Sulonen,
Teppo Varilo,
Suvi Kallio,
Anu Kemppinen,
Shaun Purcell,
Keijo Koivisto,
Pentti Tienari,
Marja-Liisa Sumelahti, [......],
Daniel B Mirel,
Stephen L Hauser,
Ludwig Kappos,
Chris Polman,
Philip L De Jager,
David A Hafler,
Mark J Daly,
Aarno Palotie,
Janna Saarela,
Leena Peltonen
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ABSTRACT: Genetic risk for multiple sclerosis (MS) is thought to involve both common and rare risk alleles. Recent GWAS and subsequent meta-analysis have established the critical role of the HLA locus and identified new common variants associated to MS. These variants have small odds ratios (ORs) and explain only a fraction of the genetic risk. To expose potentially rare, high-impact alleles, we conducted a GWAS of 68 distantly related cases and 136 controls from a high-risk internal isolate of Finland with increased prevalence and familial occurrence of MS. The top 27 loci with p < 10(-4) were tested in 711 cases and 1029 controls from Finland, and the top two findings were validated in 3859 cases and 9110 controls from more heterogeneous populations. SNP (rs744166) within the STAT3 gene was associated to MS (p = 2.75 x 10(-10), OR 0.87, confidence interval 0.83-0.91). The protective haplotype for MS in STAT3 is a risk allele for Crohn disease, implying that STAT3 represents a shared risk locus for at least two autoimmune diseases. This study also demonstrates the potential of special isolated populations in search for variants contributing to complex traits.
The American Journal of Human Genetics 02/2010; 86(2):285-91. · 10.60 Impact Factor
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Suvi P Kallio,
Eveliina Jakkula,
Shaun Purcell,
Minna Suvela,
Keijo Koivisto,
Pentti J Tienari,
Irina Elovaara,
Tuula Pirttilä, Mauri Reunanen,
Denis Bronnikov, [......],
Jan Hillert,
Frida Lundmark,
Hanne F Harbo,
Aslaug R Lorentzen,
Philip L De Jager,
Mark J Daly,
David A Hafler,
Aarno Palotie,
Leena Peltonen,
Janna Saarela
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ABSTRACT: Large case-control genome-wide association studies primarily expose common variants contributing to disease pathogenesis with modest effects. Thus, alternative strategies are needed to tackle rare, possibly more penetrant alleles. One strategy is to use special populations with a founder effect and isolation, resulting in allelic enrichment. For multiple sclerosis such a unique setting is reported in Southern Ostrobothnia in Finland, where the prevalence and familial occurrence of multiple sclerosis (MS) are exceptionally high. Here, we have studied one of the best replicated MS loci, 5p, and monitored for haplotypes shared among 72 regional MS cases, the majority of which are genealogically distantly related. The haplotype analysis over the 45 Mb region, covering the linkage peak identified in Finnish MS families, revealed only modest association at IL7R (P = 0.04), recently implicated in MS, whereas most significant association was found with one haplotype covering the C7-FLJ40243 locus (P = 0.0001), 5.1 Mb centromeric of IL7R. The finding was validated in an independent sample from the isolate and resulted in an odds ratio of 2.73 (P = 0.000003) in the combined data set. The identified relatively rare risk haplotype contains C7 (complement component 7), an important player of the innate immune system. Suggestive association with alleles of the region was seen also in more heterogeneous populations. Interestingly, also the complement activity correlated with the identified risk haplotype. These results suggest that the MS predisposing locus on 5p is more complex than assumed and exemplify power of population isolates in the identification of rare disease alleles.
Human Molecular Genetics 03/2009; 18(9):1670-83. · 7.64 Impact Factor
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ABSTRACT: A possible role of allelic variation on chromosome 19q13 in multiple sclerosis (MS) susceptibility has been suggested. We tested association of sixteen 19q13 markers with MS in 459 families. Nominally significant associations were tested in an independent set of 323 families as well as in the pooled set of 782 families. We were not able to confirm previously suggested associations with APOE, GIPR, ZNF45, ILT6 and D19S585. In the screening dataset nominally significant associations were found with D19S867 and with APOE haplotype (p=0.007 in both), but these were not replicated in the independent dataset nor in the pooled analysis of 757 families. Thus, we were not able to detect any statistically significant allelic associations. Re-sequencing based approaches may be required for elucidating the role chromosome 19q13 with MS.
Journal of neuroimmunology 03/2009; 208(1-2):119-24. · 2.84 Impact Factor
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Anu Kemppinen,
Minna Suvela,
Pentti J Tienari,
Irina Elovaara,
Keijo Koivisto,
Tuula Pirttilä, Mauri Reunanen,
Ilkka Rautakorpi,
Jan Hillert,
Frida Lundmark,
Annette Oturai,
Lars Ryder,
Hanne F Harbo,
Elisabeth G Celius,
Aarno Palotie,
Mark Daly,
Leena Peltonen,
Janna Saarela
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ABSTRACT: Single-nucleotide polymorphisms (SNPs) in the 3' region of myosin IXB (MYO9B) gene have recently been reported to associate with different inflammatory or autoimmune diseases. We monitored for the association of MYO9B variants to multiple sclerosis (MS) in four Northern European populations. First, 18 SNPs including 6 SNPs with previous evidence for association to immune disorders, were tested in 730 Finnish MS families, but no linkage or family-based association was observed. To ensure the power to detect variants with a modest effect size, we further analyzed 10 variants in 899 Finnish cases and 1325 controls, and in a total of 1521 cases and 1476 controls from Denmark, Norway and Sweden, but found no association. Our results thereby do not support a major function of the tested MYO9B variants in MS.
European journal of human genetics: EJHG 02/2009; 17(6):840-3. · 3.56 Impact Factor
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Anna-Maija Sulonen,
Suvi P Kallio,
Pekka Ellonen,
Minna Suvela,
Irina Elovaara,
Keijo Koivisto,
Tuula Pirttilä, Mauri Reunanen,
Pentti J Tienari,
Aarno Palotie,
Leena Peltonen,
Janna Saarela
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ABSTRACT: Loss-of-function mutations of DAP12 and TREM2 cause a recessively inherited disease PLOSL, manifesting in brain white matter. The genes of the DAP12-TREM2 signaling receptor are located on 19q13.12 and 6p21.1, to which linkage has been observed also in families affected by another immune-mediated demyelinating disease, MS. We have tested if allelic variation in DAP12 or TREM2 predisposes also to MS by monitoring carrier frequency of the Finnish PLOSL mutation in Finnish MS cases and by studying DAP12 and TREM2 in MS by linkage and association. To conclude, the DAP12-TREM2 complex unlikely has a role in genetic susceptibility of MS.
Journal of Neuroimmunology 12/2008; 206(1-2):86-90. · 2.96 Impact Factor
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Duodecim; lääketieteellinen aikakauskirja 02/2006; 122(18):2181-2.
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Hilde Monica F Riise Stensland,
Janna Saarela,
Denis O Bronnikov,
Maija Parkkonen,
Anne J Jokiaho,
Aarno Palotie,
Pentti J Tienari,
Marja-Liisa Sumelahti,
Irina Elovaara,
Keijo Koivisto,
Tuula Pirttilä, Mauri Reunanen,
Eric Sobel,
Leena Peltonen
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ABSTRACT: Linkage analyses have identified four major MS susceptibility loci in Finns. Here we have fine mapped the region on chromosome 5p in 28 Finnish MS families. Marker D5S416 provided the highest pairwise LOD score, and multipoint and haplotype analyses restrict the critical region to about 5.3 Mb on 5p15 between markers D5S1987 and D5S416. Ascertaining for HLA type and geographical origin indicated that families with and without the HLA DR15 risk haplotype, as well as families within and outside an internal high-risk region, contributed to the linkage to 5p, implying the general significance for this locus in Finnish MS families.
Journal of Neuroimmunology 01/2006; 170(1-2):122-33. · 2.96 Impact Factor
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Janna Saarela,
Marlena Schoenberg Fejzo,
Daniel Chen,
Saara Finnilä,
Maikki Parkkonen,
Satu Kuokkanen,
Eric Sobel,
Pentti J Tienari,
Marja-Liisa Sumelahti,
Juhani Wikström,
Irina Elovaara,
Keijo Koivisto,
Tuula Pirttilä, Mauri Reunanen,
Aarno Palotie,
Leena Peltonen
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ABSTRACT: Genome-wide linkage analyses performed in a Finnish study sample have identified four potential predisposing loci for multiple sclerosis (MS). Here we made an effort to restrict the wide linkage region on chromosome 17 with a dense set of 31 markers using multipoint linkage analyses and monitoring for shared marker alleles in MS chromosomes. We carried out the linkage analyses in 22 Finnish multiplex MS families originating from a regional subisolate that shows an exceptionally high prevalence of MS in order to minimize the genetic and environmental heterogeneity of the study sample. Thirty markers on the 23 cM initial interval gave positive pairwise LOD scores. We monitored for shared haplotypes among affected family members within a family, and identified an approximately 4 cM region flanked by the markers D17S1792 and ATA43A10 in 17 out of the 22 families (77.3%). The multipoint linkage analyses using Genehunter and SIMWALK 2.40 provided further evidence for the same 4 cM region, for example a maximal multipoint NPL score of 5.98 (P<0.0002). We observed nominal evidence for association to MS, with one marker flanking the shared region, and this association was replicated in the additional set of families. Using the combined power of linkage, association and shared haplotype analyses, we were thus able to restrict the MS locus on chromosome 17q from 23 cM to a 4 cM region covering a physical interval of approximately 2.5 Mb. Thus, this study describes the restriction of an MS locus outside the HLA region into a segment approachable by molecular tools.
Human Molecular Genetics 10/2002; 11(19):2257-67. · 7.64 Impact Factor
