Genome-wide linkage analysis and evidence of gene-by-gene interactions in a sample of 362 multiplex Parkinson disease families

Nathan Pankratz, William C. Nichols, Sean K. Uniacke, Cheryl Halter, Jill Murrell, Alice Rudolph, Clifford W. Shults, P. Michael Conneally, Tatiana Foroud, Daniel Truong, Mayank Pathak, An Tran, Robert Rodnitzky, Judith Dobson, William Koller, William Weiner, Kelly Lyons, Roger Kurlan, Debra Berry, John BertoniCarolyn Peterson, Wayne Martin, Marguerite Wieler, Paul Tuite, Robyn Schacherer, Karen Marder, Juliette Harris, Joseph Jankovic, Christine Hunter, Anthony Lang, Galit Kleimer-Fisman, Anette Nieves, Julie So, Stewart Factor, Sharon Evans, Bala Manyam, Brian Wulbrecht, Francis Walker, Victoria Hunt, Mark F. Gordon, Joanna Hamman, Un Jang Kang, Joan Young, Karen Blindauer, Jeannine Petit, Jayaraman Rao, Maureen Cook, Mark Stacy, Kelli Williamson, Rachel Saunders Pullman, Karyn Boyar, Maureen Leehey, Theresa Derian, Paul Gordon, Joan Werner, Brad Racette, Laura Good, David Simon, Lisa Scollins, Donna Schwieterman, Richard Dewey, Melinda Meacham, James Sutton, Brad Hutchinson, Mandar Jog, Cheryl Horn, Kapil Sethi, Joan Carpenter, Paul Atchison, Susan Rolli, Lewis Sudarsky, Claire Corwin, Miodrag Velickovic, Sabrina Phipps, Tanya Simuni, Annette Kaczmarek, Neal Hermanowicz, Shari Niswonger, Andrew Feigin, Barbara Shannon, Vincent Calabrese, Peggy Roberge, Hunter Homes, Lisa Shulman, Kelly Dustin, Todd Ajax, Janet Mannetter, G. David Podskalny, Lisa Giffin, Ryan Uitti, Margaret Foster Turk

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130 Scopus citations


Parkinson disease (PD) is the second most common neurodegenerative disorder. We studied 754 affected individuals, comprising 425 sibling pairs, to identify PD susceptibility genes. Screening of the parkin gene was performed in a subset of the sample having earlier age of PD onset or a positive LOD score with a marker in the parkin gene. All subjects were evaluated using a rigorous neurological assessment. Two diagnostic models were considered for genome-wide, non-parametric linkage analyses. Model I included only those individuals with a more stringent diagnosis of verified PD (216 sibling pairs) and resulted in a maximum LOD score of 3.4 on chromosome 2. Model II included all affected individuals (425 sibling pairs) and yielded a LOD score of 3.1 on the X chromosome. Our large sample was then employed to test for gene-by-gene (epistatic) interactions. A genome screen using the 23 families with PD patients having a mutation in only one allele of the parkin gene detected evidence of linkage to chromosome 10 (LOD = 2.3). The 85 families with a very strong family history of PD were employed in a genome screen and, in addition to strong evidence of linkage to chromosome 2 (LOD = 4.9), also produced a LOD of 2.4 on chromosome 14. A genome screen performed in the 277 families without a strong family history of PD detected linkage to chromosomes 10 (LOD = 2.4) and X (LOD = 3.2). These findings demonstrate consistent evidence of linkage to chromosomes 2 and X and also support the hypothesis that gene-by-gene interactions are important in PD susceptibility.

Original languageEnglish
Pages (from-to)2599-2608
Number of pages10
JournalHuman molecular genetics
Issue number20
StatePublished - Oct 15 2003


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