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Resequencing and fine-mapping of the chromosome 12q13-14 locus associated with multiple sclerosis refines the number of implicated genes.

Abstract

Multiple sclerosis (MS) is a common chronic inflammatory disease of the central nervous system. Susceptibility to the disease is affected by both environmental and genetic factors. Genetic factors include haplotypes in the histocompatibility complex (MHC) and over 50 non-MHC loci reported by genome-wide association studies. Amongst these, we previously reported polymorphisms in chromosome 12q13-14 with a protective effect in individuals of European descent. This locus spans 288 kb and contains 17 genes, including several candidate genes which have potentially significant pathogenic and therapeutic implications. In this study, we aimed to fine-map this locus. We have implemented a two-phase study: a variant discovery phase where we have used next-generation sequencing and two target-enrichment strategies [long-range polymerase chain reaction (PCR) and Nimblegen's solution phase hybridization capture] in pools of 25 samples; and a genotyping phase where we genotyped 712 variants in 3577 healthy controls and 3269 MS patients. This study confirmed the association (rs2069502, P = 9.9 × 10(-11), OR = 0.787) and narrowed down the locus of association to an 86.5 kb region. Although the study was unable to pinpoint the key-associated variant, we have identified a 42 (genotyped and imputed) single-nucleotide polymorphism haplotype block likely to harbour the causal variant. No evidence of association at previously reported low-frequency variants in CYP27B1 was observed. As part of the study we compared variant discovery performance using two target-enrichment strategies. We concluded that our pools enriched with Nimblegen's solution phase hybridization capture had better sensitivity to detect true variants than the pools enriched with long-range PCR, whilst specificity was better in the long-range PCR-enriched pools compared with solution phase hybridization capture enriched pools; this result has important implications for the design of future fine-mapping studies.

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  • Authors+Show Affiliations

    ,

    University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Qld. 4102, Australia.

    , , , , ,

    Source

    Human molecular genetics 22:11 2013 Jun 01 pg 2283-92

    MeSH

    Adult
    Case-Control Studies
    Chromosome Mapping
    Chromosomes, Human, Pair 12
    Female
    Genetic Loci
    Genome-Wide Association Study
    Genotype
    Humans
    Linkage Disequilibrium
    Male
    Middle Aged
    Multiple Sclerosis
    Mutation
    Polymorphism, Single Nucleotide
    Sequence Analysis, DNA
    Young Adult

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    23406874

    Citation

    Cortes, Adrian, et al. "Resequencing and Fine-mapping of the Chromosome 12q13-14 Locus Associated With Multiple Sclerosis Refines the Number of Implicated Genes." Human Molecular Genetics, vol. 22, no. 11, 2013, pp. 2283-92.
    Cortes A, Field J, Glazov EA, et al. Resequencing and fine-mapping of the chromosome 12q13-14 locus associated with multiple sclerosis refines the number of implicated genes. Hum Mol Genet. 2013;22(11):2283-92.
    Cortes, A., Field, J., Glazov, E. A., Hadler, J., Stankovich, J., & Brown, M. A. (2013). Resequencing and fine-mapping of the chromosome 12q13-14 locus associated with multiple sclerosis refines the number of implicated genes. Human Molecular Genetics, 22(11), pp. 2283-92. doi:10.1093/hmg/ddt062.
    Cortes A, et al. Resequencing and Fine-mapping of the Chromosome 12q13-14 Locus Associated With Multiple Sclerosis Refines the Number of Implicated Genes. Hum Mol Genet. 2013 Jun 1;22(11):2283-92. PubMed PMID: 23406874.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Resequencing and fine-mapping of the chromosome 12q13-14 locus associated with multiple sclerosis refines the number of implicated genes. AU - Cortes,Adrian, AU - Field,Judith, AU - Glazov,Evgeny A, AU - Hadler,Johanna, AU - ,, AU - Stankovich,Jim, AU - Brown,Matthew A, Y1 - 2013/02/12/ PY - 2013/2/15/entrez PY - 2013/2/15/pubmed PY - 2014/1/1/medline SP - 2283 EP - 92 JF - Human molecular genetics JO - Hum. Mol. Genet. VL - 22 IS - 11 N2 - Multiple sclerosis (MS) is a common chronic inflammatory disease of the central nervous system. Susceptibility to the disease is affected by both environmental and genetic factors. Genetic factors include haplotypes in the histocompatibility complex (MHC) and over 50 non-MHC loci reported by genome-wide association studies. Amongst these, we previously reported polymorphisms in chromosome 12q13-14 with a protective effect in individuals of European descent. This locus spans 288 kb and contains 17 genes, including several candidate genes which have potentially significant pathogenic and therapeutic implications. In this study, we aimed to fine-map this locus. We have implemented a two-phase study: a variant discovery phase where we have used next-generation sequencing and two target-enrichment strategies [long-range polymerase chain reaction (PCR) and Nimblegen's solution phase hybridization capture] in pools of 25 samples; and a genotyping phase where we genotyped 712 variants in 3577 healthy controls and 3269 MS patients. This study confirmed the association (rs2069502, P = 9.9 × 10(-11), OR = 0.787) and narrowed down the locus of association to an 86.5 kb region. Although the study was unable to pinpoint the key-associated variant, we have identified a 42 (genotyped and imputed) single-nucleotide polymorphism haplotype block likely to harbour the causal variant. No evidence of association at previously reported low-frequency variants in CYP27B1 was observed. As part of the study we compared variant discovery performance using two target-enrichment strategies. We concluded that our pools enriched with Nimblegen's solution phase hybridization capture had better sensitivity to detect true variants than the pools enriched with long-range PCR, whilst specificity was better in the long-range PCR-enriched pools compared with solution phase hybridization capture enriched pools; this result has important implications for the design of future fine-mapping studies. SN - 1460-2083 UR - https://www.unboundmedicine.com/medline/citation/23406874/Resequencing_and_fine_mapping_of_the_chromosome_12q13_14_locus_associated_with_multiple_sclerosis_refines_the_number_of_implicated_genes_ L2 - https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddt062 DB - PRIME DP - Unbound Medicine ER -