Genetics and Multiple Sclerosis: Future Prospects Workshop

September 8-10, 2003
Washington D.C.

Introduction

Multiple sclerosis (MS) is a complex genetic disorder. Over the years, a series of genes have been implicated in disease susceptibility or manifestation, but no conclusive outcomes were obtained. Technological advances and the imminent publication of a human haplotype map renewed interest in MS genetics and made a meeting on this topic timely and opportune. The workshop assembled an international group of MS and autoimmune disease geneticists in order to assess the current status of MS genetics research and to evaluate how progress can be expedited in this exciting field. To this aim, barriers to progress and needed collaboration were explored as were possible solutions and priorities.

The workshop was jointly organized and sponsored by the National Institute of Neurological Disorders and Stroke and the National Multiple Sclerosis Society, Dr. John Todd, University of Cambridge, UK, served as meeting chair.

Background

Despite decades of research on the genetics of MS, a definite identification of genetic risk factors for this disease has been elusive. It is speculated that up to 50 or more genes may contribute to MS and that each individual gene's contribution may be weak. Although a series of candidate genes have been proposed over the years, the large samples sizes required have prevented unequivocal, statistically significant identification of a particular gene. The strongest association to date lies within the chromosomal region for HLA. MS geneticists traditionally employed linkage analysis which requires large samples sizes that most often cannot be obtained. Newer approaches such as haplotype mapping, SNP analysis and admixture studies are expected to suffice with smaller samples sizes. Four independent whole genome scans and the study of genetic risk factors in isolated populations led to the identification of only partially overlapping genomic regions. Consolidation and confirmation of these findings might only be feasible with large-scale, international projects.

Discussion

The first meeting day was dedicated to an assessment of the current knowledge in the field. Presentations were given by research teams from Finland, the UK, Canada, Australia, and the US and included a discussion of their current approaches, the technologies they are employing, and of ongoing collaborations. The described designs included whole genome scans and candidate gene searches (Drs. Sadovnick, Sawcer, and Haines), some of these completed in isolated/ ethnically homogenous populations (Drs. Peltonen and Kilpatrick). Admixture studies proposed to take advantage of populations with mixed racial composition and the fact that MS occurs with higher frequency in individuals with Northern European ancestry (Drs. Oksenberg and Reich). The newly available human haplotype map is the basis for efforts to identify MS susceptibility regions via the single nucleotide changes or SNPs that characterize specific haplotypes or blocks of genes (Drs. Hudson, Altshuler, Daly and Hauser).

Day 2 was dedicated to a debate of the barriers to progress, possible solutions and the need for collaboration. The challenge of collecting sample sizes large enough to achieve statistical power was argued, a challenge that also impacts the need for confirmation of the varying results obtained by the different research teams. Most participants felt that the time was right to launch an intense effort in mapping MS susceptibility genes and that a central repository for DNA and data could speed such efforts. The collection of consistently prepared samples of high quality and of controls was emphasized. Both new studies and the replication of previous results would benefit from such a collection. The potential danger of domination of a central repository by a single mega-consortium was raised as was the fear that repository funding would shift funds from smaller single lab-based genetics projects. NIDDK's diabetes and inflammable bowel disease repositories were mentioned as positive examples for how data ownership, sharing and trust issues can be addressed.

Recommendations/Conclusions

After a six year hiatus, this important meeting brought together all major MS genetics research teams and opened up new lines of communication. As a result, new strategies are now under consideration that might speed the search for MS genes. The proposed strategies include a) data sharing among the various groups, and joint data analyses; b) the creation of a central repository for data from all MS genetics groups; c) sharing of existing samples and collection of additional DNA samples as required for gene discovery in this complex genetic disorder; d) the development of more innovative, cost-effective ways of genotyping.

Participants