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


Cortes, A and Field, J and Glazov, EA and Hadler, J and Stankovich, J and Brown, MA and Baxter, A and Kermode, AG and Taylor, B and Booth, DR and Mason, D and Stewart, GJ and Butzkueven, H and Charlesworth, J and Wiley, J and Lechner-Scott, J and Field, J and Tajouri, L and Griffiths, L and Slee, M and Brown, MA and Moscato, P and Scott, RJ and Broadley, S and Vucic, S and Kilpatrick, TJ and Carroll, WM, 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. 2283-2292. ISSN 0964-6906 (2013) [Refereed Article]

Copyright Statement

Copyright 2013 The authors

DOI: doi:10.1093/hmg/ddt062


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. © The Author 2013. Published by Oxford University Press. All rights reserved.

Item Details

Item Type:Refereed Article
Research Division:Biomedical and Clinical Sciences
Research Group:Neurosciences
Research Field:Central nervous system
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Stankovich, J (Dr Jim Stankovich)
UTAS Author:Taylor, B (Professor Bruce Taylor)
UTAS Author:Charlesworth, J (Dr Jac Charlesworth)
ID Code:84924
Year Published:2013
Web of Science® Times Cited:14
Deposited By:Menzies Institute for Medical Research
Deposited On:2013-06-06
Last Modified:2017-11-07

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