Abstract
Parkinson disease (PD) is a common neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity, and postural instability, as well as by a clinically significant response to treatment with levodopa. Mutations in the α-synuclein gene have been found to result in autosomal dominant PD, and mutations in the parkin gene produce autosomal recessive juvenile-onset PD. We have studied 203 sibling pairs with PD who were evaluated by a rigorous neurological assessment based on (a) inclusion criteria consisting of clinical features highly associated with autopsy-confirmed PD and (b) exclusion criteria highly associated with other, non-PD pathological diagnoses. Families with positive LOD scores for a marker in an intron of the parkin gene were prioritized for parkin-gene testing, and mutations in the parkin gene were identified in 22 families. To reduce genetic heterogeneity, these families were not included in subsequent genome-screen analysis. Thus, a total of 160 multiplex families without evidence of a parkin mutation were used in multipoint nonparametric linkage analysis to identify PD-susceptibility genes. Two models of PD affection status were considered: model I included only those individuals with a more stringent diagnosis of verified PD (96 sibling pairs from 90 families), whereas model II included all examined individuals as affected, regardless of their final diagnostic classification (170 sibling pairs from 160 families). Under model I, the highest LOD scores were observed on chromosome X (LOD score 2.1) and on chromosome 2 (LOD score 1.9). Analyses performed with all available sibling pairs (model II) found even greater evidence of linkage to chromosome X (LOD score 2.7) and to chromosome 2 (LOD score 2.5). Evidence of linkage was also found to chromosomes 4, 5, and 13 (LOD scores >1.5). Our findings are consistent with those of other linkage studies that have reported linkage to chromosomes 5 and X.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 124-135 |
| Number of pages | 12 |
| Journal | American Journal of Human Genetics |
| Volume | 71 |
| Issue number | 1 |
| DOIs | |
| State | Published - 2002 |
Bibliographical note
Funding Information:This project was supported by National Institutes of Health grant R01 NS37167. We thank two anonymous reviewers for their helpful suggestions. We thank the subjects for their participation in this research study. PSG Investigators are as follows: Steering Committee—Lawrence Golbe, M.D. (UMDNJ Robert Wood Johnson Medical Center, New Brunswick, NJ); William Koller, M.D. (University of Miami, Miami); Karen Marder, M.D. (Columbia-Presbyterian Medical Center, New York); Frederick Marshall, M.D., David Oakes, Ph.D., Alice Rudolph, Ph.D., and Aileen Shinaman, J.D. (University of Rochester, Rochester, NY); and Eric Siemers (Eli Lilly & Company, Indianapolis). Participating Investigators and Coordinators—Julie Carter, R.N., M.D., A.N.P., Richard Camicioli, M.D., and Pamela Andrews, R.N. (Oregon Health & Science University, Portland); Joanne Wojcieszek, M.D., and Joann Belden, R.N. (Indiana University School of Medicine, Indianapolis); Magali Frenandez, M.D., Jean Hubble, M.D., and Carson Reider, Ph.D. (Ohio State University, Columbus); Ali Rajput, M.D., Alex Rajput, M.D., and Theresa Shirley, R.N. (Saskatoon Health District Board, Saskatoon, Saskatchewan, Canada); Michael Panisset, M.D., and Jean Hall, R.N. (McGill Centre for Studies in Aging, Verdun, Quebec, Canada); Tilak Mendis, M.D., David A. Grimes, M.D., and Peggy Gray, R.N., B.S.C.N. (Ottawa Civic Hospital, Ottawa, Ontario, Canada); Carmen Serrano Ramos, M.D., and Sandra Roque, R.N. (University of Puerto Rico School of Medicine, San Juan); Stephen Reich, M.D., and Becky Dunlop, R.N. (Johns Hopkins University, Baltimore); Robert Hauser, M.D., Juan Sanchez-Ramos, M.D., Theresa Zesiewicz, M.D., and Holly Delgado, R.N. (University of South Florida, Tampa); Ronald Pfeiffer, M.D., and Brenda Pfeiffer, R.N., B.S.N. (University of Tennessee-Memphis, Memphis); Joseph Friedman, M.D., Hubert Fernandez, M.D., and Margaret Lannon, R.N., M.S. (Brown University, Pawtucket, RI); Cliff Shults, M.D., and Deborah Fontaine, R.N.C., G.N.P. (University of California–San Diego, San Diego); Lauren Seeberger, M.D., Christopher O'Brien, M.D., and Deborah Judd, R.N. (Colorado Neurological Institute, Englewood); Rajesh Pahwa, M.D., and Stephanie Thomas, L.P.N. (Kansas University Medical Center, Kansas City); Lawrence Elmer, M.D., Ph.D., and Kathy Davis, R.N., M.S.N. (Medical College of Ohio, Toledo); Danna Jennings, M.D., Kenneth Marek, M.D., and Susan Mendick, M.P.H. (Institute for Neurodegenerative Disorders, New Haven, CT); Daniel Truong, M.D., Mayank Pathak, M.D., and Anhoa Tran, R.N. (Parkinson's & Movement Disorder Institute, Fountain Valley, CA); Robert Rodnitzyk, M.D., and Judith Dobson, R.N. (University of Iowa, Iowa City); Roger Kurlan, M.D., and Debra Berry, M.S.N., N.P. (University of Rochester Medical Center, Rochester, NY); Paul Tuite, M.D., and Robyn Schacher, R.N. (University of Minnesota/Hennepin County Medical Center, Minneapolis); Michael Aminoff, M.D., F.R.C.P., and Mariann DiMinno (University of California San Francisco, San Francisco); Karen Marder, M.D., and Juliette Harris, M.S., Ph.D. (Columbia-Presbyterian Medical Center, New York); Peter Lewitt, M.D., and Maryan DeAngelis, R.N. (Clinical Neuroscience Center, West Bloomfield, MI); William Koller, M.D., William Weiner, R.N., and Kelly Lyons, Ph.D. (University of Miami, Miami); Wayne Martin, M.D., and Marguerite Wieler, B.S.C., P.T. (University of Alberta, Edmonton, Alberta, Canada); Joseph Jankovic, M.D., and Christine Hunter, R.N. (Baylor College of Medicine, Houston); John Bertoni, M.D., Ph.D., and Carolyn Peterson, R.N. (Creighton University, Omaha); Stewart Factor, D.O., and Sharon Evans, L.P.N. (Albany Medical College, Albany, NY); Francis Walker, M.D., and Victoria Hunt, R.N. (Wake Forest University School of Medicine, Winston-Salem, NC); Un Jung Kang, M.D., and Shirley Uy (University of Chicago, Chicago); Mark Stacy, M.D., and Kelli Williamson, R.N., (Barrow Neurological Institute, Phoenix); David Simon, M.D., and Lisa Scollins, R.N. (Beth Israel Deaconess Medical Center, Boston); Karen Brindauer, M.D., and Jeannine Petit, C.N.R.N., G.N.P.C. (Medical College of Wisconsin, Milwaukee); Bala Manyam, M.D., and Patricia Simpson, R.N., B.S.N. (Scott & White Hospital, Temple, TX); Anette Nieves, M.D., and Julie So (Toronto Western Hospital, Toronto, Ontario, Canada); Miodrag Velickovic, M.D., and Sabrina Phipps (Mount Sinai Medical Center, New York); Mark F. Gordon, M.D., and Joanna Hamann (Long Island Jewish Medical Center, New Hyde Park, NY); Maureen Leehey, M.D., and Sharon Culver, A.N.P. (University of Colorado Health Sciences Center, Denver); Paul Gordon, M.D., and Joan Werner (University of New Mexico, Albuquerque); Jayaraman Rao, M.D., and Maureen Cook, R.N., B.S.N. (LSU Medical Center, New Orleans); Arif Dalvi, M.D., and Donna Schweiterman (University of Cincinnati Medical Center, Cincinnati); Brad Racette, M.D. (Washington University, St. Louis); Kapil Sethi, M.D., and Joan Carpenter, R.N. (Medical College of Georgia, Augusta); Lewis Sudarsky, M.D., and Claire Corwin, P.A.C., B.S. (Brigham & Women's Hospital, Boston); Rachel Saunders Pullman, M.D., and Karyn Boyer (Beth Israel Medical Center, New York); Tanya Simuni, M.D., and Michele Wolff (Northwestern University Medical School, Chicago); Richard Dewey, M.D., and Melinda Jones, R.N., B.S.N. (University of Texas Southwestern Medical Center, Dallas); Neal Hermanowicz, M.D. (University of California Irvine, Irvine); Andrew Feigin, M.D., and Barbara Shannon, R.N. (North Shore University Hospital, Manhasset, NY); Vincent Calabresse, M.D., and Peggy Roberge, R.N. (McGuire Research Institute, Richmond); James Sutton, M.D., and Brad Hutchinson, C.C.R.C. (California Medical Clinic for Movement Disorders, Oxnard); Todd Ajax, M.D., and Janet Mannetter, R.N. (McFarland Clinic, Mary Greely Hospital, Ames, IA); G. David Podakalny, M.D., and Lisa Giffin, L.P.N. (New Jersey School of Osteopathic Medicine, Stratford); Oksana Suchowersky, M.D., and Mary Lou Klimek, R.N., B.N., M.A. (University of Calgary, Calgary, Alberta, Canada); Ryan Uitti, M.D., and Margaret Foster Turk, R.N. (Mayo Clinic Jacksonville, Jacksonville); Lisa Shulman, M.D., and Kelly Dustin, R.N. (University of Maryland School of Medicine, Baltimore); and Biostatistics and Clinical Trials Coordination Center Staff—David Oakes Ph.D., Arthur Watts, B.S., Antai Wang, M.A., Tori Ross, M.A., Susan Bennett, A.A.S., and Elaine Julian-Baros (University of Rochester, Rochester, NY).