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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

Beena Akolkar, Ph.D.
NIDDK
National Institutes of Health
  Janine AltmÜller, M.D.
Max Delbrueck Center
Gene Mapping Center
 
David M. Altshuler, M.D., Ph.D.
Department of Molecular Biology
Massachusetts General Hospital
  Sergio E. Baranzini, Ph.D.
Department of Neurology
University of California San Francisco
 
Lisa F. Barcellos, Ph.D.
Department of Neurology
University of California
  Robert Baughman, Ph.D.
NINDS
National Institutes of Health Neuroscience Center
 
Kevin G. Becker, Ph.D.
NIA
National Institutes of Health
  Sara M. Bernstein
Research Programs Department
National Multiple Sclerosis Society
 
Timothy Coetzee, Ph.D.
Research Training Programs
National Multiple Sclerosis Society
  David E. Comings, M.D.
Department of Medical Genetics
Beckman Research Institute
City of Hope National Medical Center
 
Alastair Compston, M.D.
Neurology Unit, Addenbrooke's Hospital
University of Cambridge
  Mark Daly, Ph.D.
Whitehead/Pfizer Computational Biology
Whitehead Institute
 
Philip De Jager, M.D., Ph.D.
Center for Neurologic Diseases
Brigham and Women's Hospital
  Pierre Duquette, M.D.
Service de Neurologie
Université de Montréal
 
George Cornell Ebers, M.D.
Department of Clinical Neurology
University of Oxford
Radcliffe Infirmary
  Tom Esch, Ph.D.
NIAID
National Institutes of Health
 
Simon J. Foote, Ph.D., MBBS
Department of Genetics and Bioinformatics
The Walter and Eliza Hall Institute of Medical Research
  Peter K. Gregersen, M.D.
Center for Genomics and Human Genetics
North Shore Long Island Jewish Research Institute
Department of Medicine
 
Simon G. Gregory, Ph.D.
Center for Human Genetis
Duke University Medical Center
  David Hafler, M.D.
Department of Neurology
Harvard Medical School
 
Jonathan L. Haines, Ph.D.
Program in Human Genetics
Molecular Physiology and Biophysics
Vanderbilt University Medical Center
  Stephen L. Hauser, M.D.
Department of Neurology
Univ. of California, San Francisco
 
William F. Hickey, M.D.
Department of Pathology
Dartmouth Medical School
  Jan Hillert, M.D., Ph.D.
Division of Neurology
Neurotec
Karolinska Institute
 
Paul M. Hoffman, M.D.
Clinical Neuroscience Research Program
VA Medical Center
  Thomas J. Hudson, M.D.
Genome Quebec Innovation Centre
McGill University
 
Bernadette Kalman, M.D., Ph.D.
Department of Neurology
MS Research Center
St. Luke's Roosevelt Hospital Center
  Trevor J. Kilpatrick, Ph.D., MBBS
Development and Neurobiology
The Walter and Eliza Hall Institute of Medical Research
 
Thomas P. Leist, M.D., Ph.D.
Department of Neurology
Thomas Jefferson University
  Fred D. Lublin, M.D.
Department of Neurology
Corinne Goldsmith Dickinson
Center for MS
Mount Sinai Medical Center
 
Jorge R. Oksenberg, Ph.D.
Department of Neurology
Univ of California, San Francisco
  Patricia O'Looney, Ph.D.
Biomedical Research Programs
National Multiple Sclerosis Society
 
Thomas Olsson, M.D., Ph.D.
Neuro & Immunology Unit
Department of Clinical Neurosciences Karolinska Hospital
  Leena Peltonen, M.D., Ph.D.
Department of Molecular Medicine and
Department of Medical Genetics
National Public Health Insitute and
University of Helsinki
 
Audrey Penn, M.D.
NINDS
National Institutes of Health
  Margaret A. Pericak-Vance, Ph.D.
Center for Human Genetis
Duke University Medical Center
 
Alan C. Peterson, Ph.D.
Department of Neurology and Neurosurgery
McGill University
Royal Victoria Hospital
  Bruce Rannala, Ph.D.
Department of Medical Genetics
University of Alberta
 
David E. Reich, Ph.D.
Department of Genetics
Whitehead Institute
MIT Center for Genome Research
  Stephen C. Reingold, Ph.D.
Research Programs Department
National Multiple Sclerosis Society
 
John D. Rioux, Ph.D.
Inflammatory Disease Research Group
Whitehead Institute
MIT Center for Genome Research
  Justin P. Rubio, Ph.D.
MS Genetics Group
The Division of Genetics & Bioinformatics
The Walter & Eliza Hall Institute of Medical Research
 
A. Dessa Sadovnick, Ph.D.
Department of Medical Genetics
Division of Neurology
University of British Columbia
  Stephen James Sawcer, Ph.D.
Department of Neurology
University of Cambridge
Addenbrooke's Hospital
 
Silke Schmidt, Ph.D.
Center for Human Genetics
Duke University Medical Center
  Graeme J. Stewart, Ph.D.
Department of Immunology & Allergy Research
Westmead Millennium Institute
University of Sydney
 
Danilo Tagle, Ph.D.
NINDS
National Institutes of Health
Neuroscience Center
  John A. Todd, Ph.D.
Department of Medical Genetics
University of Cambridge
Cambridge Institute for Medical Research
 
Patricia H. Turner
Office of Science Policy and Planning
NINDS
National Institutes of Health
  Ursula Utz, Ph.D.
NINDS
National Institutes of Health
Neuroscience Center
 
Emilia Vitale, Ph.D.
Gene Mapping Laboratory
Department of Microbiology & Molecular Genetics
UMDNJ New Jersey Medical School
  Leslie P. Weiner, M.D.
Department of Neurology
KECK School of Medicine
University of Southern California
 
Brian G. Weinshenker, M.D.
Department of Neurology
Mayo Clinic, Rochester
  Caroline C. Whitacre, Ph.D.
Department of Molecular Virology, Immunology and Medical Genetics
Ohio State University
 
Jerry S. Wolinsky, M.D.
Department of Neurology
University of Texas
Health Science Center, Houston
   

Last updated August 19, 2011