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Human Molecular Genetics Advance Access originally published online on August 12, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 20 2599-2608
DOI: 10.1093/hmg/ddg270
© 2003 Oxford University Press

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

Nathan Pankratz1, William C. Nichols2, Sean K. Uniacke2, Cheryl Halter1, Jill Murrell1, Alice Rudolph3, Clifford W. Shults4, P. Michael Conneally1, Tatiana Foroud1,* and the Parkinson Study Group

1Department of Medical and Molecular Genetics, Indiana University Medical Center, Indianapolis, IN, USA, 2Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA, 3Department of Neurology, University of Rochester, Rochester, NY, USA and 4Department of Neurosciences, University of California, La Jolla, CA and the VA San Diego Healthcare System, San Diego, CA, USA

Received May 30, 2003; Revised July 29, 2003; Accepted August 1, 2003

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.

* To whom correspondence should be addressed at: Indiana University School of Medicine, Department of Medical and Molecular Genetics (IB 130), 975 West Walnut Street, Indianapolis, IN 46202-5251, USA. Tel: +1 3172781291; Fax: +1 3172742387; Email: tforoud{at}iupui.edu


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