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International Multiple Sclerosis (MS) Genetics Consortium

 
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IMSGC group meeting, 27th March 2009, Wellcome Trust Sanger Institute, Cambridge, UK 

 

As is the case for most neurodegenerative diseases, there is strong evidence to support the idea that MS is a disease with a complex genetic background upon which environmental triggers act. Although many groups sought to identify these genetic risk factors, prior to 2007 only one (within the MHC) was known. Most early efforts used a linkage approach and in hindsight were underpowered and therefore incapable of identifying what we now understand to be the individually modest effects of each risk factor.

The International MS Genetics Consortium (IMSGC) was formed in 2003 with the specific aim of addressing this challenge. By taking advantage of emerging high throughput genotyping tools, pooling patient cohorts, and sharing financial resources, the IMSGC embarked on a comprehensive assessment of genetic influences on MS. With the early support of a few major private donors, the National MS Society, the Penates Foundation and the NIH, we collected patient records and DNA samples, evaluated competing technology platforms (see Human Molec. Genetics, 2004), completed a high density screen for linkage (which confirmed the need to move on to larger association studies; see Am. J. Hum. Genet., 2005) and further explored the nature of the MHC influence on MS (see Annals Neurology, 2007).

With further funding from the NMSS and others, the Consortium then undertook a major new Whole Genome Association (WGA) study using a total of 12,360 subjects, and highlighted 17 SNPs or interest in 12 loci (see NEJM, 2007). In particular (and in addition to the MHC signal), two SNPs in intron 1 of the IL2Ra gene (also known as CD25) on chromosome 10p15 and a SNP in exon 6 of IL7RA gene on chromosome 5p13 showed highly significant evidence of association. Both of these signals were confirmed by others.  

This study demonstrated that in principle the WGA approach was effective, and highlighted the power of collaboration and the strength of the IMSGC. It also confirmed the likelihood that many other MS risk loci (of similarly individually modest risk) exist and would only be revealed by studies of considerably higher statistical power. Indeed, these advances notwithstanding, in 2007 knowledge of MS genetics remained incomplete. Between them the known MS risk loci accounted for only a fraction of the inherited susceptibility to the disease.

With this in mind in 2008 the Consortium embarked on a major expansion of its genetics program. By more than doubling the number of groups that make up the Consortium, and thanks to major funding and support from the UK Wellcome Trust, we launched a new WGA study, aiming to study at least 10,000 well characterized patients and a similar number of controls. In light of the expected modest individual gene effects and the likelihood of clinical and locus heterogeneity, stringent replication in an independent patient population was also planned.

By late 2009, thanks to the support of the Wellcome Trust and the expertise of the Sanger Centre in Cambridge, UK the primary scan of 10,000 patients was underway. Throughout 2010 we undertook the long and careful process of analyzing this huge data set. This work, subsequently published August 2011 (Nature 476, 214-218), replicated almost all of the previously described associations and identified a further 29 risk loci.

In parallel, with the support of the National MS Society, we started collecting a new cohort of patients willing to help us with the critical replication stage. In collaboration with 18 MS clinics across the US and the UK we set ourselves the goal of recruiting a further 10,000 patients. By early 2012 we surpassed our target with more than 11,000 volunteers recruited and set about designing a custom genotyping chip with which to undertake the genotyping of the replication phase of the work. 

As of October 2012, genotyping a total of 40,000+ subjects is set to begin.

We are nearing the end of our nine-year, international effort to establish a comprehensive atlas of common genetic variations that affect susceptibility to MS and to identify novel disease candidate genes, pathways and networks, leading to testable hypotheses as to which are the causative allelic variants determining susceptibility to MS. We will use this emerging and more refined model of pathogenesis to determine putative targets to be tested in our drug discovery program and to perform risk assessments for individuals at risk of MS.

The IMSGC has a formal structure including a small Governance Group, a Strategy Group that directs the day-to-day research, and a large Members Group. We are committed to making all of our data available to any appropriate researcher world wide. To find out what data is available and how to apply, and for a list of our members and resources, please visit our web site at www.imsgenetics.org.