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

Adrian Cortes, Judith Field, Evgeny A. Glazov, Johanna Hadler, Jim Stankovich, Matthew A. Brown, Alan Baxter, Allan G. Kermode, Bruce Taylor, David R. Booth, Deborah Mason, Graeme J. Stewart, Helmut Butzkueven, Jac Charlesworth, James Wiley, Jeannette Lechner-Scott, Judith Field, Lotti Tajouri, Lyn R. Griffiths, Mark Slee & 7 others Matthew A. Brown, Pablo Moscato, Rodney J. Scott, Simon Broadley, Steve Vucic, Trevor J. Kilpatrick, William M. Carroll

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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 targetenrichment 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.

Original languageEnglish
Pages (from-to)2283-2292
Number of pages10
JournalHuman Molecular Genetics
Volume22
Issue number11
DOIs
Publication statusPublished - Jun 2013

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Chromosomes, Human, Pair 14
Multiple Sclerosis
Polymerase Chain Reaction
Haplotypes
25-Hydroxyvitamin D3 1-alpha-Hydroxylase
Genes
Genome-Wide Association Study
Disease Susceptibility
Major Histocompatibility Complex
Single Nucleotide Polymorphism
Chronic Disease
Central Nervous System
Therapeutics

Cite this

Cortes, A., Field, J., Glazov, E. A., Hadler, J., Stankovich, J., Brown, M. A., ... Carroll, W. M. (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), 2283-2292. https://doi.org/10.1093/hmg/ddt062
Cortes, Adrian ; Field, Judith ; Glazov, Evgeny A. ; Hadler, Johanna ; Stankovich, Jim ; Brown, Matthew A. ; Baxter, Alan ; Kermode, Allan G. ; Taylor, Bruce ; Booth, David R. ; Mason, Deborah ; Stewart, Graeme J. ; Butzkueven, Helmut ; Charlesworth, Jac ; Wiley, James ; Lechner-Scott, Jeannette ; Field, Judith ; Tajouri, Lotti ; Griffiths, Lyn R. ; Slee, Mark ; Brown, Matthew A. ; Moscato, Pablo ; Scott, Rodney J. ; Broadley, Simon ; Vucic, Steve ; Kilpatrick, Trevor J. ; Carroll, William M. / Resequencing and fine-mapping of the chromosome 12q13-14 locus associated with multiple sclerosis refines the number of implicated genes. In: Human Molecular Genetics. 2013 ; Vol. 22, No. 11. pp. 2283-2292.
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title = "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 targetenrichment 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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Cortes, A, Field, J, Glazov, EA, Hadler, J, Stankovich, J, Brown, MA, Baxter, A, Kermode, AG, Taylor, B, Booth, DR, Mason, D, Stewart, GJ, Butzkueven, H, Charlesworth, J, Wiley, J, Lechner-Scott, J, Field, J, Tajouri, L, Griffiths, LR, Slee, M, Brown, MA, Moscato, P, Scott, RJ, Broadley, S, Vucic, S, Kilpatrick, TJ & Carroll, WM 2013, '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, pp. 2283-2292. https://doi.org/10.1093/hmg/ddt062

Resequencing and fine-mapping of the chromosome 12q13-14 locus associated with multiple sclerosis refines the number of implicated genes. / Cortes, Adrian; Field, Judith; Glazov, Evgeny A.; Hadler, Johanna; Stankovich, Jim; Brown, Matthew A.; Baxter, Alan; Kermode, Allan G.; Taylor, Bruce; Booth, David R.; Mason, Deborah; Stewart, Graeme J.; Butzkueven, Helmut; Charlesworth, Jac; Wiley, James; Lechner-Scott, Jeannette; Field, Judith; Tajouri, Lotti; Griffiths, Lyn R.; Slee, Mark; Brown, Matthew A.; Moscato, Pablo; Scott, Rodney J.; Broadley, Simon; Vucic, Steve; Kilpatrick, Trevor J.; Carroll, William M.

In: Human Molecular Genetics, Vol. 22, No. 11, 06.2013, p. 2283-2292.

Research output: Contribution to journalArticleResearchpeer-review

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 - Stankovich, Jim

AU - Brown, Matthew A.

AU - Baxter, Alan

AU - Kermode, Allan G.

AU - Taylor, Bruce

AU - Booth, David R.

AU - Mason, Deborah

AU - Stewart, Graeme J.

AU - Butzkueven, Helmut

AU - Charlesworth, Jac

AU - Wiley, James

AU - Lechner-Scott, Jeannette

AU - Field, Judith

AU - Tajouri, Lotti

AU - Griffiths, Lyn R.

AU - Slee, Mark

AU - Brown, Matthew A.

AU - Moscato, Pablo

AU - Scott, Rodney J.

AU - Broadley, Simon

AU - Vucic, Steve

AU - Kilpatrick, Trevor J.

AU - Carroll, William M.

PY - 2013/6

Y1 - 2013/6

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 targetenrichment 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.

AB - 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 targetenrichment 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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U2 - 10.1093/hmg/ddt062

DO - 10.1093/hmg/ddt062

M3 - Article

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SP - 2283

EP - 2292

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

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