Monday, 18 March 2013

Research: finding rare MS susceptibility genes

#MSBlog: There is more to our genome than meets the eye; a new data analysis technique uncovers rare variants.

Epub: Lin et al. Identity-by-Descent Mapping to Detect Rare Variants Conferring Susceptibility to Multiple Sclerosis. PLoS One. 2013;8(3):e56379. doi: 10.1371/journal.pone.0056379.

Background: Genome-wide association studies (GWAS) have identified around 60 common variants associated with multiple sclerosis (MS), but these loci only explain a fraction of the heritability of MS. Some missing heritability may be caused by rare variants that have been suggested to play an important role in the aetiology of complex diseases such as MS. However current genetic and statistical methods for detecting rare variants are expensive and time consuming. 

Methods: 'Population-based linkage analysis' (PBLA) or so called identity-by-descent (IBD) mapping is a novel way to detect rare variants in extant GWAS datasets. This study employed BEAGLE fastIBD to search for rare MS variants utilising IBD mapping in a large GWAS dataset of 3,543 cases and 5,898 controls. 

Results: They identified a genome-wide significant linkage signal on chromosome 19 (LOD = 4.65; p = 1.9×10). Network analysis of cases and controls sharing haplotypes on chromosome 19 further strengthened the association as there are more large networks of cases sharing haplotypes than controls. This linkage region includes a cluster of zinc finger genes of unknown function. Analysis of genome wide transcriptome data suggests that genes in this zinc finger cluster may be involved in very early developmental regulation of the CNS. 

Conclusions: This study indicates that BEAGLE fastIBD allowed identification of rare variants in large unrelated population with moderate computational intensity. Even with the development of whole-genome sequencing, IBD mapping still may be a promising way to narrow down the region of interest for sequencing priority.


"A large part of MS is in our genes, finding these has been a long and hard job. Despite a large number of variants that can explain a part of the heritability of MS a large component is missing. Genomics experts believe this is missing part is due to rare variants, i.e. variants that are found in less than 1% of the population. This study describes a new method for searching for these variants in existing data sets. Why is this important? We need to be able identify members of the population that are at very high-risk of getting MS so that we can target prevention at them."

7 comments:

  1. Not being a geneticist, I'm curious how this squares up with this research article?

    https://www.sciencedirect.com/science/article/pii/S0022510X12003590
    A patient with both narcolepsy and multiple sclerosis in association with Pandemrix vaccination.

    Abstract

    Narcolepsy with cataplexy is caused by a selective loss of hypocretin-producing neurons, but symptomatic narcolepsy can also result from hypothalamic and brainstem lesions caused by multiple sclerosis (MS).

    We report a previously healthy man who developed clinical and laboratory verified narcolepsy without having any indication of hypothalamic lesions and MS after vaccination against the influenza H1N1 with Pandemrix. HLA typing showed both DRB1*15:01, associated with MS and DQB1*06:02, associated with narcolepsy.

    The genetic susceptibility in this patient makes it tempting to speculate upon an immune-mediated mechanism and a common etiology for both diseases in this patient.

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    Replies
    1. Have to say this is an n = 1 so is it chance or causally related event.

      It has been know for some time that Nacrcolepsy is associated with the HLA just as it has been known for some time that MS , diabetes, arthritis etc are associated with certain HLA variants. In the abstract the associations to the two conditions are related to expression of different HLA variants one to a HLA-DR variant (MS) the other to HLA-DQ variant (Nacrolepsy). Is the MS related to the vaccination? or could we have written because the person had eaten baked beans. The chance to the second possibility is probably as likely as the first and the link to the vaccination is probably a chance event

      Delete
  2. Published yesterday. One can only hope...

    http://www.technologyreview.com/news/512216/a-cancer-gene-therapy-activated-by-a-pill/

    ReplyDelete
    Replies
    1. Hope dashed

      This is delivery of Interleukin 12.
      (a) Interleukin 12 is an augmenter of immune response which you want to destroy the cancer. In MS you want an inhibitor
      (b) Interleukin 12 blockage did not inhibit MS.

      On plus side you could use the approach with a different cytokine so I guess you could do beta interferon and then take pill to turn it on. So beta interferon with only one injection.

      Systemic cytokines can on balance be bad news, they will either cause regulators as they are produced in balance or you can get side effects.
      You may want the cytokine to be made in the brain also

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  3. Yes, but then you have this UK study:
    UK study confirms GSK flu shot link to rare sleep disorder
    http://tinyurl.com/c4222yw

    LONDON (Reuters) - GlaxoSmithKline's Pandemrix swine flu vaccine has been linked to cases of the rare sleep disorder narcolepsy in children in a scientific study in England that confirms similar findings elsewhere in Europe.

    So this is more than N = 1

    ReplyDelete
    Replies
    1. The n of 1 was narcolepsy and MS the thing you are saying is pandemix vaccine and nacrolepsy

      Delete

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