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Complete Genomic Screen in Parkinson Disease
Evidence for Multiple Genes
William K. Scott, PhD;
Martha A. Nance, MD;
Ray L. Watts, MD;
Jean P. Hubble, MD;
William C. Koller, MD;
Kelly Lyons, PhD;
Rajesh Pahwa, MD;
Matthew B. Stern, MD;
Amy Colcher, MD;
Bradley C. Hiner, MD;
Joseph Jankovic, MD;
William G. Ondo, MD;
Fred H. Allen, Jr, MD;
Christopher G. Goetz, MD;
Gary W. Small, MD;
Donna Masterman, MD;
Frank Mastaglia, MD;
Nigel G. Laing, MD;
Jeffrey M. Stajich, PA-C;
Brandon Slotterbeck, BS;
Michael W. Booze, BS;
Robert C. Ribble, BS;
Evadnie Rampersaud, MSPH;
Sandra G. West, BS;
Rachel A. Gibson, PhD;
Lefkos T. Middleton, MD;
Allen D. Roses, MD;
Jonathan L. Haines, PhD;
Burton L. Scott, PhD, MD;
Jeffery M. Vance, PhD, MD;
Margaret A. Pericak-Vance, PhD
JAMA. 2001;286:2239-2244.
Context The relative contribution of genes vs environment in idiopathic Parkinson disease (PD) is controversial. Although genetic studies have identified 2 genes in which mutations cause rare single-gene variants of PD and observational studies have suggested a genetic component, twin studies have suggested that little genetic contribution exists in the common forms of PD.
Objective To identify genetic risk factors for idiopathic PD.
Design, Setting, and Participants Genetic linkage study conducted 1995-2000 in which a complete genomic screen (n = 344 markers) was performed in 174 families with multiple individuals diagnosed as having idiopathic PD, identified through probands in 13 clinic populations in the continental United States and Australia. A total of 870 family members were studied: 378 diagnosed as having PD, 379 unaffected by PD, and 113 with unclear status.
Main Outcome Measures Logarithm of odds (lod) scores generated from parametric and nonparametric genetic linkage analysis.
Results Two-point parametric maximum parametric lod score (MLOD) and multipoint nonparametric lod score (LOD) linkage analysis detected significant evidence for linkage to 5 distinct chromosomal regions: chromosome 6 in the parkin gene (MLOD = 5.07; LOD = 5.47) in families with at least 1 individual with PD onset at younger than 40 years, chromosomes 17q (MLOD = 2.28; LOD = 2.62), 8p (MLOD = 2.01; LOD = 2.22), and 5q (MLOD = 2.39; LOD = 1.50) overall and in families with late-onset PD, and chromosome 9q (MLOD = 1.52; LOD = 2.59) in families with both levodopa-responsive and levodopa-nonresponsive patients.
Conclusions Our data suggest that the parkin gene is important in early-onset PD and that multiple genetic factors may be important in the development of idiopathic late-onset PD.
Author Affiliations: Department of Medicine and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC (Drs W. K. Scott, B. L. Scott, Vance, and Pericak-Vance, Messrs Stajich, Slotterbeck, Booze, and Ribble, and Mss Rampersaud and West); Struthers Parkinson Center, Golden Valley, Minn (Dr Nance); Department of Neurology, Emory University School of Medicine, Atlanta, Ga (Dr Watts); Department of Neurology, Ohio State University, Columbus (Dr Hubble); Department of Neurology, University of Miami School of Medicine, Miami, Fla (Drs Koller and Lyons); Department of Neurology, University of Kansas Medical Center, Kansas City (Dr Pahwa); Department of Neurology, University of Pennsylvania Health System, Philadelphia (Drs Stern and Colcher); Department of Neurology, Marshfield Clinic, Marshfield, Wis (Dr Hiner); Department of Neurology, Baylor College of Medicine, Houston, Tex (Drs Jankovic and Ondo); Carolina Neurologic Clinic, Charlotte, NC (Dr Allen); Department of Neurological Sciences, Rush-Presbyterian-St Luke's Hospital, Chicago, Ill (Dr Goetz); Departments of Psychiatry and Behavioral Science and Neurology, University of California, Los Angeles (Drs Small and Masterman); Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Perth (Drs Mastaglia and Laing); GlaxoSmithKline Research and Development, Greenford, Middlesex, England (Drs Gibson and Middleton); GlaxoSmithKline Research and Development, Research Triangle Park, NC (Dr Roses); and Program in Human Genetics, Vanderbilt University Medical Center, Nashville, Tenn (Dr Haines).
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