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 6707 Democracy Boulevard, Room 681 Bethesda, MD 20892 Tel: (301) 594-8812 Fax: (301) 480-3503 Email: akolkarb@extra.niddk.nih.gov		Janine AltmÜller, M.D. Max Delbrueck Center Gene Mapping Center Robert-RÖssle-Str.10 13125 Berlin, Germany Tel: 49-30-9406-3512 Fax: 49-30-9406-3147 Email: janine@ltmueller.de
David M. Altshuler, M.D., Ph.D. Department of Molecular Biology Massachusetts General Hospital 50 Blossom St., Wellman 831 Boston, MA 02114 Tel: 617- 726-5940 Fax: 617-726-5937 Email: altshuler@molbio.mgh.harvard.edu cc: :kinzer@molbio.mgh.harvard.edu		Sergio E. Baranzini, Ph.D. Department of Neurology University of California San Francisco 513 Parnassus Avenue, Room S-256 San Francisco, CA 94143 Tel: (415) 476-3136 Fax: (415) 476-5229 Email: sebaran@cgl.ucsf.edu
Lisa F. Barcellos, Ph.D. Department of Neurology University of California 513 Parnassus Avenue, S-258 San Francisco, CA 94143-0435 Tel: (415) 476-3136 Fax: (415) 476-5229 Email: barcello@genepi.ucsf.edu		Robert Baughman, Ph.D. NINDS National Institutes of Health Neuroscience Center 6001 Executive Boulevard Room 2137 Bethesda, MD 20892 Tel: (301) 496-1779 Fax: (301) 402-1501 Email: baughmar@ninds.nih.gov
Kevin G. Becker, Ph.D. NIA National Institutes of Health 333 Cassel Drive, Room 207 TRIAD Technology Center Baltimore, MD 21224 Tel: (410) 558-8360 Fax: (410) 558-8281 Email: beckerk@grc.nia.nih.gov		Sara M. Bernstein Research Programs Department National Multiple Sclerosis Society 733 Third Avenue New York, NY 10025 Tel: (212) 476-0419 Fax: (212) 986-7981 Email: sara.bernstein@nmss.org
Timothy Coetzee, Ph.D. Research Training Programs National Multiple Sclerosis Society 733 Third Avenue, 6th Floor New York, NY 10017 Tel: (212) 476-0478 Fax: (212) 986-7981 Email: timothy.coetzee@nmss.org cc: paula.grant@nmss.org		David E. Comings, M.D. Department of Medical Genetics Beckman Research Institute City of Hope National Medical Center 1500 E. Durate Rd. Duarte, CA 91010 Tel: (626) 359-8111 ext. 62631 Fax: (626) 302-8980 Email: dcomings@coh.org Secondary: dcomings@earthlink.net
Alastair Compston, M.D. Neurology Unit, Addenbrooke's Hospital University of Cambridge Hills Road Cambridge, CB2 2QQ United Kingdom Tel: 44-1223-217091 Fax: 44-1223-336941 Email: alastair.compston@medschl.cam.ac.uk		Mark Daly, Ph.D. Whitehead/Pfizer Computational Biology Whitehead Institute Nine Cambridge Center Cambridge, MA 02142-1479 Tel: (617) 252-1931 Email: mjdaly@genome.wi.mit.edu
Philip De Jager, M.D., Ph.D. Center for Neurologic Diseases Brigham and Women's Hospital 77 Avenue Louis Pasteur, HIM Boston, MA 02115 Tel. (617) 525-5330 Fax: (617) 525-5305 Email: pdejager@partners.org		Pierre Duquette, M.D. Service de Neurologie Université de Montréal 1560 Sherbrooke East Hôpital Notre-Dame du CHUM 3e Pav. Deschamps H-3135 Montréal, Québec, H2L-4M1 Canada Tel: (514) 890-8212 Fax: (514) 412-7668 Email: pierre.duquette.chum@ssss.gouv.qc.ca
George Cornell Ebers, M.D. Department of Clinical Neurology University of Oxford Radcliffe Infirmary Woodstock Road Oxford, England OX2 6HE United Kingdom Tel: +44-0-1865-228568/228579 Fax: +44-0-1865-790493 Email: george.ebers@clneuro.ox.ac.uk cc: dominico.luscombe@clneuro.ox.ac.uk		Tom Esch, Ph.D. NIAID National Institutes of Health 6610 Rockledge Drive Bethesda, MD 20892 Tel: (301) 496-7104 Email: tesch@niaid.nih.gov
Simon J. Foote, Ph.D., MBBS Department of Genetics and Bioinformatics The Walter and Eliza Hall Institute of Medical Research 1A Royal Parade Parkville, Victoria 3050 Australia Tel: +61 3-9345-2611 Fax: +61 3- 9347-0852 Email: foote@wehi.edu.au cc: joy@wehi.edu.au		Peter K. Gregersen, M.D. Center for Genomics and Human Genetics North Shore Long Island Jewish Research Institute Department of Medicine 350 Community Drive Manhasset, New York 11030 Tel: (516) 562-1542 Fax: (516) 562-1153 Email: peterg@nshs.edu
Simon G. Gregory, Ph.D. Center for Human Genetis Duke University Medical Center 595 La Salle Street Durham, NC 27705 Tel: (919) 684-0726 Fax: (919) 684-0924 Email: sgregory@chg.duhs.duke.edu		David Hafler, M.D. Department of Neurology Harvard Medical School 77 Ave Louis Pasteur, Room 786 Boston, MA 02115 Tel: (617) 525-5330 Fax: (617) 525-5333 Email: hafler@cnd.bwh.harvard.edu cc: egoldings@rics.bwh.harvard.edu
Jonathan L. Haines, Ph.D. Program in Human Genetics Molecular Physiology and Biophysics Vanderbilt University Medical Center 519 Light Hall Nashville, TN 37232-0700 Tel: (615) 343-8551 Fax: (615) 343-8619 Email: jonathan@phg.mc.vanderbilt.edu cc: tangela@phg.mc.vanderbilt.edu		Stephen L. Hauser, M.D. Department of Neurology Univ. of California, San Francisco 505 Parnassus Avenue, M798 San Francisco, CA 94143-0114 Tel: (415) 476-9211 Fax: (415) 476-3428 Email: hauser@itsa.ucsf.edu cc: kbolen@itsa.ucsf.edu
William F. Hickey, M.D. Department of Pathology Dartmouth Medical School Borwell Building - DHMC Lebanon, NH 03756 Tel: (603) 650-4805 Fax: (603) 650-14845 Email: William.f.hickey@dartmouth.edu		Jan Hillert, M.D., Ph.D. Division of Neurology Neurotec Karolinska Institute University Hospital R54 Stockholm, SE-141 86 Sweden Tel: +46-8-5858-2056 Fax: +46-8-5858-7080 Email: jan.hillert@neurotec.ki.se Secondary: jan.hillert@cnsf.ki.se
Paul M. Hoffman, M.D. Clinical Neuroscience Research Program VA Medical Center 10 North Greene Street Baltimore, MD 21201 Tel: (410) 605-7000, ext. 6410 Fax: (410) 605-7906 Email: paul.hoffman2@med.va.gov		Thomas J. Hudson, M.D. Genome Quebec Innovation Centre McGill University 740 Dr. Penfield Avenue, Room 7105 Montreal, Quebec, H3A 1A4 Canada Tel: 514-398-3311 x00385 Fax: 514-398-1790 Email: tom.hudson@mcgill.ca Secondary: tjhudson@med.mcgill.ca cc: jenny.koulis@mail.mcgill.ca
Bernadette Kalman, M.D., Ph.D. Department of Neurology MS Research Center St. Luke's Roosevelt Hospital Center Columbia University 432 West 58th Street New York, NY 10019 Tel: (212) 523-8676 Fax: (212) 523-8859 Email: bk33@drexel.edu Secondary: bkalman@chpnet.org		Trevor J. Kilpatrick, Ph.D., MBBS Development and Neurobiology The Walter and Eliza Hall Institute of Medical Research 1G Royal Parade Parkville, Victoria, 3050 Australia. Tel: 61 3 9345 2546 Fax: 61 3 9347 0852 Email: kilpatrick@wehi.edu.au
Thomas P. Leist, M.D., Ph.D. Department of Neurology Thomas Jefferson University 1025 Walnut St., #310 Philadelphia, PA 19107 Tel: 215-955-7310 Fax: 215-503-2990 Email: Thomas.Leist@jefferson.edu		Fred D. Lublin, M.D. Department of Neurology Corinne Goldsmith Dickinson Center for MS Mount Sinai Medical Center 5 East 98th Street New York, NY 10029 Tel: (212) 241-6854 Fax: (212) 423-0440 Email: fred.lublin@mssm.edu
Jorge R. Oksenberg, Ph.D. Department of Neurology Univ of California, San Francisco 513 Parnassus Avenue, Room S-258 San Francisco, CA 94143-0435 Tel: (415) 476-1335 Fax: (415) 476-5229 Email: oksen@itsa.ucsf.edu		Patricia O'Looney, Ph.D. Biomedical Research Programs National Multiple Sclerosis Society 733 Third Avenue, 6th Floor New York, NY 10017 Tel: (212) 476-0413 Fax: (212) 986-7981 Email: patricia.olooney@nmss.org
Thomas Olsson, M.D., Ph.D. Neuro & Immunology Unit Department of Clinical Neurosciences Karolinska Hospital CMM L8:04 17176, Stockholm, Sweden Phone: 46-8-51776242 Fax: 46-8-51776248 Email: tomas.olsson@cmm.ki.sc		Leena Peltonen, M.D., Ph.D. Department of Molecular Medicine and Department of Medical Genetics National Public Health Insitute and University of Helsinki Haartmaninkatu 8 (PO Box 104) FIN-00290, Helsinki, Finland Tel: 358-9-4744-8393 Fax: 358-9-4744-8480 Email: leena.peltonen@ktl.fi Email: sari.kivikko@ktl.fi
Audrey Penn, M.D. NINDS National Institutes of Health 31 Center Drive, Room 8A52 Bethesda, MD 20892 Tel: (301) 496-3167 Fax: (301) 496-0296 Email: penna@ninds.nih.gov		Margaret A. Pericak-Vance, Ph.D. Center for Human Genetis Duke University Medical Center P. O. Box 3445 Durham, NC 27710 Tel: (919) 684-2063 Fax: (919) 684-0910 Email: mpv@chg.mc.duke.edu Email: cheryl.harris@duke.edu
Alan C. Peterson, Ph.D. Department of Neurology and Neurosurgery McGill University Royal Victoria Hospital 687 Pine Avenue West Montreal, Canada H3A 1A1 Tel: (514) 842-1231, ext. 35846 Fax: (514)843-1478 Email: alan@devbiol2.molonc.mcgill.ca		Bruce Rannala, Ph.D. Department of Medical Genetics University of Alberta 8-39 Medical Sciences Building Edmonton, Alberta T6G 2H7 Canada Tel: (780) 492-3139 Fax: (780) 492-1354 Email: brannala@ualberta.ca
David E. Reich, Ph.D. Department of Genetics Whitehead Institute MIT Center for Genome Research One Kendall Square, Building 300 Cambridge, MA 02142 Tel: (617) 252-1695 Fax: (617) 252-1902 Email: reich@genome.wi.mit.edu		Stephen C. Reingold, Ph.D. Research Programs Department National Multiple Sclerosis Society 733 Third Avenue New York, NY 10017 Tel: (212) 476-0411 Fax: (212) 986-7981 Email: stephen.reingold@nmss.org
John D. Rioux, Ph.D. Inflammatory Disease Research Group Whitehead Institute MIT Center for Genome Research One Kendall Square, Building 300 Cambridge, MA 02139-1561 Tel: (617) 252-1917 Fax: (617) 252-1902 Email: rioux@genome.wi.mit.edu Email: garrett@genome.wi.mit.edu		Justin P. Rubio, Ph.D. MS Genetics Group The Division of Genetics & Bioinformatics The Walter & Eliza Hall Institute of Medical Research IG Royal Parade Parkville, Victoria 3050 Australia Tel: 61 3-9345-2481 Fax: 61 3-9347-0852 Email: rubio@wehi.edu.au
A. Dessa Sadovnick, Ph.D. Department of Medical Genetics Division of Neurology University of British Columbia 5312 Laburnum Street Vancouver, British Columbia, V6M 3S6 Canada Tel: (604) 822-5670 Fax: (604) 822-7362 Email: sadovnik@infinet.net		Stephen James Sawcer, Ph.D. Department of Neurology University of Cambridge Addenbrooke's Hospital Box 165, Hills Road Cambridge CB2 2QQ United Kingdom Tel: +44--1223-216073 Fax: +44--1223-336941 Email: sjs1016@mole.bio.cam.ac.uk
Silke Schmidt, Ph.D. Center for Human Genetics Duke University Medical Center Box 3445 Durham, NC 27705 Tel: (919) 684-0624 Fax: (919) 684-0925 Email: silke.schmidt@duke.edu cc: rshealy@chg.duhs.duke.edu		Graeme J. Stewart, Ph.D. Department of Immunology & Allergy Research Westmead Millennium Institute University of Sydney Westmead NSW 2145 Australia Tel: 61 2-9845-6791 Fax: 61 2-9891-3889 Email: stewartg@westgate.wh.usyd.edu.au
Danilo Tagle, Ph.D. NINDS National Institutes of Health Neuroscience Center 6001 Executive Boulevard Room 2133 Bethesda, MD 20892 Tel: (301) 496-5745 Fax: (301) 402-1501 Email: tagled@ninds.nih.gov		John A. Todd, Ph.D. Department of Medical Genetics University of Cambridge Cambridge Institute for Medical Research Cambridge, C82 2XY United Kingdom Tel: 44- 1223 762101 Fax: 44 1223 762102 Email: john.todd@cimr.cam.ac.uk cc: judy.brown@cimr.cam.ac.uk
Patricia H. Turner Office of Science Policy and Planning NINDS National Institutes of Health Building 31, Room 8A03 9000 Rockville Pike Bethesda, MD 20892-2540 Tel: (301) 496- 9271 Fax: (301) 480-9172 Email: pt13n@nih.gov		Ursula Utz, Ph.D. NINDS National Institutes of Health Neuroscience Center 6001 Executive Boulevard Room 2134 Bethesda, MD 20892 Tel: (301) 496-1431 Fax: (301) 480-2424 Email: utzu@ninds.nih.gov
Emilia Vitale, Ph.D. Gene Mapping Laboratory Department of Microbiology & Molecular Genetics UMDNJ New Jersey Medical School 185 South Orange Avenue MSB F-649 P.O. Box 1709 Newark, NJ 07103 Tel: (973) 972-5984 Fax: (973) 972-1114 Email: vitaleem@umdnj.edu		Leslie P. Weiner, M.D. Department of Neurology KECK School of Medicine University of Southern California 1975 Zonal Avenue, KAM 410 Los Angeles, CA 90033 Tel: (323) 442-3020 Fax: (323) 442-3015 Email: lweiner@usc.edu cc: apeikis@usc.edu
Brian G. Weinshenker, M.D. Department of Neurology Mayo Clinic, Rochester 200 First Street Southwest Rochester, MN 55905 Tel: (507) 538-1039 Fax: (507) 266-4419 Email: weinb@mayo.edu Email: ccbbott.denise@mayo.edu		Caroline C. Whitacre, Ph.D. Department of Molecular Virology, Immunology and Medical Genetics Ohio State University 2078 Graves Hall 333 West 10th Avenue Columbus, OH 43210-9805 Tel: (614) 292-5889 Fax: (614) 292-9805 Email: whitacre.3@osu.edu cc: Feasel.3@osu.edu
Jerry S. Wolinsky, M.D. Department of Neurology University of Texas Health Science Center, Houston 6431 Fannin Street, Suite 7044 Houston, TX 77030 Tel: (713) 500-7048 Fax: (713) 500-7041 Email: jswolinsky@aol.com