Association of Single-Nucleotide Polymorphisms of the Tau Gene With Late-Onset Parkinson Disease
- Eden R. Martin, PhD;
- 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;
- Robert C. Ribble, BS;
- Michael W. Booze, BS;
- Allison Rogala, BS;
- Michael A. Hauser, PhD;
- Fengyu Zhang, PhD;
- Rachel A. Gibson, PhD;
- Lefkos T. Middleton, MD;
- Allen D. Roses, MD;
- Jonathan L. Haines, PhD;
- Burton L. Scott, MD;
- Margaret A. Pericak-Vance, PhD;
- Jeffery M. Vance, PhD, MD
- Author Affiliations: Department of Medicine and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC (Drs Martin, W. K. Scott, Hauser, Zhang, B. L. Scott, Pericak-Vance, and Vance, Messrs Stajich, Ribble, and Booze, and Ms Rogala); 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).
Abstract
Context The human tau gene, which promotes assembly of neuronal microtubules, has been associated with several rare neurologic diseases that clinically include parkinsonian features. We recently observed linkage in idiopathic Parkinson disease (PD) to a region on chromosome 17q21 that contains the tau gene. These factors make tau a good candidate for investigation as a susceptibility gene for idiopathic PD, the most common form of the disease.
Objective To investigate whether the tau gene is involved in idiopathic PD.
Design, Setting, and Participants Among a sample of 1056 individuals from 235 families selected from 13 clinical centers in the United States and Australia and from a family ascertainment core center, we tested 5 single-nucleotide polymorphisms (SNPs) within the tau gene for association with PD, using family-based tests of association. Both affected (n = 426) and unaffected (n = 579) family members were included; 51 individuals had unclear PD status. Analyses were conducted to test individual SNPs and SNP haplotypes within the tau gene.
Main Outcome Measure Family-based tests of association, calculated using asymptotic distributions.
Results Analysis of association between the SNPs and PD yielded significant evidence of association for 3 of the 5 SNPs tested: SNP 3, P = .03; SNP 9i, P = .04; and SNP 11, P = .04. The 2 other SNPs did not show evidence of significant association (SNP 9ii, P = .11, and SNP 9iii, P = .87). Strong evidence of association was found with haplotype analysis, with a positive association with one haplotype (P = .009) and a negative association with another haplotype (P = .007). Substantial linkage disequilibrium (P<.001) was detected between 4 of the 5 SNPs (SNPs 3, 9i, 9ii, and 11).
Conclusions This integrated approach of genetic linkage and positional association analyses implicates tau as a susceptibility gene for idiopathic PD.
