Genetic variation in the KIF1B locus influences susceptibility to multiple sclerosis

Aulchenko, Yurii S.; Hoppenbrouwers, I A; Ramagopalan, Sreeram; Broer, Linda; Jafari, Naghmeh; Hillert, Jan; Link, Jenny; Lundström, Wangko; Greiner, Eva; Sadovnick, A. Dessa; Goossens, Dirk; Broeckhoven, Christine Van; Del-Favero, Jurgen; Ebers, George C.; Oostra, Ben A.; Duijn, Cornelia M. van; Hintzen, Rogier Q.

doi:10.1038/ng.251

Cited by 166 publications

(117 citation statements)

References 15 publications

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“…Associations at class I suggested by case-control studies to be independent of HLA class II (15) were not sustained once account was taken of linkage disequilibrium (8,16). In addition to the MHC, modest associations with other non-MHC loci have been found for IL7R (17,18), IL2R (19), EVI5 (20) and KIF1B (21). The latter is the largest of these with an odds ratio (OR) of 1.34 in sporadic MS and 1.74 in multiplex families (22).…”

mentioning

confidence: 90%

Epistasis amongHLA-DRB1, HLA-DQA1,andHLA-DQB1loci determines multiple sclerosis susceptibility

Lincoln

Ramagopalan

Chao

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

152

128

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Multiple sclerosis (MS), a common central nervous system inflammatory disease, has a major heritable component. Susceptibility is associated with the MHC class II region, especially HLA-DRB5*0101-HLA-DRB1*1501-HLA-DQA1*0102-HLA-DQB1*0602 haplotypes (hereafter DR2), which dominate genetic contribution to MS risk. Marked linkage disequilibrium (LD) among these loci makes identification of a specific locus difficult. The once-leading candidate, HLA-DRB1*15, localizes to risk, neutral, and protective haplotypes. HLA-DRB1*15 and HLA-DQB1*0602, nearly always located together on a small ancestral chromosome segment, are strongly MS-associated. One intervening allele on this haplotype, viz. HLA-DQA1*0102, shows no primary MS association. Two Canadian cohorts (n ‫؍‬ 830 and n ‫؍‬ 438 trios) genotyped for HLA-DRB1, HLA-DQA1 and HLA-DQB1 alleles were tested for association using TDT. To evaluate epistasis involving HLA-DRB1*15, transmissions from HLA-DRB1*15-negative parents were stratified by the presence/absence of HLA-DRB1*15 in affected offspring. All 3 alleles contribute to MS susceptibility through novel epistatic interactions. HLA-DQA1*0102 increased disease risk when combined with HLA-DRB1*1501 in trans, thereby unambiguously implicating HLA-DQ in MS susceptibility. Three-locus haplotypes demonstrated that HLA-DRB1*1501 and HLA-DQB1*0602 each influence risk. Transmissions of rare morcellated DR2 haplotypes showed no interaction with HLA-DQA1*0102. Incomplete haplotypes bearing only HLA-DRB1*1501 or HLA-DQB1*0602 did not predispose to MS. Balanced reciprocal transmission distortion can mask epistatic allelic association. These findings implicate epistasis among HLA class II alleles in human immune responses generally, provide partial explanation for intense linkage disequilibrium in the MHC, have relevance to animal models, and demonstrate key roles for DR2-specific interactions in MS susceptibility. MHC disease associations may be more generally haplotypic or diplotypic.genetics ͉ MHC ͉ linkage disequilibrium

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mentioning

confidence: 90%

Epistasis amongHLA-DRB1, HLA-DQA1,andHLA-DQB1loci determines multiple sclerosis susceptibility

Lincoln

Ramagopalan

Chao

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

152

128

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“…A SNP within KIF1B was recently associated with MS susceptibility in datasets from the Netherlands, Sweden, and Canada (Aulchenko et al, 2008). KIF1B encodes a kinesin protein believed to transport mitochondria and synaptic vesicles along axonal microtubules.…”

Section: Kinesin Family 1b (Kif1b)mentioning

confidence: 99%

Genetics of primary progressive multiple sclerosis

Cree

2014

Handbook of Clinical Neurology

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“…4 This is advantageous for GWAS, as the increase in risk makes it easier to identify a variant using a relatively small sample. 4,6 In addition, the increased homozygosity facilitates the identification of recessive variants. 7,8 Sardinia is considered an old genetic isolate, based on historical and archeological records, 9 genetic analyses 10,11 and the increased prevalence of certain disorders.…”

Section: Introductionmentioning

confidence: 99%

Dissecting the genetic make-up of North-East Sardinia using a large set of haploid and autosomal markers

Pardo

Piras²,

Asproni³

et al. 2012

Eur J Hum Genet

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Sardinia has been used for genetic studies because of its historical isolation, genetic homogeneity and increased prevalence of certain rare diseases. Controversy remains concerning the genetic substructure and the extent of genetic homogeneity, which has implications for the design of genome-wide association studies (GWAS). We revisited this issue by examining the genetic make-up of a sample from North-East Sardinia using a dense set of autosomal, Y chromosome and mitochondrial markers to assess the potential of the sample for GWAS and fine mapping studies. We genotyped individuals for 500K single-nucleotide polymorphisms, Y chromosome markers and sequenced the mitochondrial hypervariable (HVI-HVII) regions. We identified major haplogroups and compared these with other populations. We estimated linkage disequilibrium (LD) and haplotype diversity across autosomal markers, and compared these with other populations. Our results show that within Sardinia there is no major population substructure and thus it can be considered a genetically homogenous population. We did not find substantial differences in the extent of LD in Sardinians compared with other populations. However, we showed that at least 9% of genomic regions in Sardinians differed in LD structure, which is helpful for identifying functional variants using fine mapping. We concluded that Sardinia is a powerful setting for genetic studies including GWAS and other mapping approaches.

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Genetic variation in the KIF1B locus influences susceptibility to multiple sclerosis

Cited by 166 publications

References 15 publications

Epistasis amongHLA-DRB1, HLA-DQA1,andHLA-DQB1loci determines multiple sclerosis susceptibility

Epistasis amongHLA-DRB1, HLA-DQA1,andHLA-DQB1loci determines multiple sclerosis susceptibility

Genetics of primary progressive multiple sclerosis

Dissecting the genetic make-up of North-East Sardinia using a large set of haploid and autosomal markers

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