International Multiple Sclerosis (MS) Genetics Consortium

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 have sought to identify these genetic risk factors and many have been proposed, with the exception of the well known association with polymorphic variants within the MHC, none have stood the test of time. 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, the Consortium then undertook a major new WGA study using a 931 trio (plus further controls) design for the primary screen, and 7,136 subjects for the replication phase. The combined analysis (of 12,360 subjects) 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 in parallel and subsequently confirmed by others.  

Whereas this WGA study highlighted the power of collaboration and the strength of the IMSGC, it also confirmed the likelihood that many other loci of similar impact exist and will only be revealed by studies of considerably higher statistical power. Indeed, these advances notwithstanding, knowledge of MS genetics remains incomplete. Between them these loci account for no more than 50% of the inherited susceptibility to the disease.

With this in mind the Consortium recently 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 and the National MS Society, we are undertaking a new WGA study. At least 10,000 well characterized patients (already collected) and a similar number of controls will be typed in the primary scan using the new Illumina 610 quad chip and 60,000 additional probes for determining CNVs. We expect this high-resolution genome scan to expand and refine the list of genetic elements of MS susceptibility. However, in light of the modest individual gene effects and the likelihood of clinical and locus heterogeneity, stringent replication in an independent dataset of adequate statistical power constitutes an essential final step in generating unequivocal results.

As of June 2008, we are still determining the size and nature of this replication phase (for which funds are currently being sought). Our working assumption is that it will also employ 10,000 cases and 10,000 controls, each to be typed for the top 1% of hits from the primary scan. Thus two major goals are currently being pursued. First, we are building the infrastructure and funding to expand our shared DNA repository by 10,000 new study participants. Secondly, we will apply stringent quality control filters to the primary scan data and use those results as the starting point for our multi-analytical approach to map unambiguous signals of association in subjects with MS.  

This work will establish a comprehensive atlas of common genetic variations that affect susceptibility to MS and will 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.

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.imsgc.org.