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NEUROLOGY 2003;61:1557-1561
© 2003 American Academy of Neurology

A haplotype at the PARK3 locus influences onset age for Parkinson’s disease

The GenePD study

S. Karamohamed, PhD, A. L. DeStefano, PhD, J. B. Wilk, DSc, C. M. Shoemaker, BS, L. I. Golbe, MD, M. H. Mark, MD, A. M. Lazzarini, PhD, O. Suchowersky, MD, N. Labelle, BN, M. Guttman, MD, L. J. Currie, PhD, G. F. Wooten, MD, M. Stacy, MD, M. Saint-Hilaire, MD, R. G. Feldman, MD, K. M. Sullivan, MPH, G. Xu, MS, R. Watts, MD, J. Growdon, MD, M. Lew, MD, C. Waters, MD, P. Vieregge, MD, P. P. Pramstaller, MD, C. Klein, MD, B. A. Racette, MD, J. S. Perlmutter, MD, A. Parsian, PhD, C. Singer, MD, E. Montgomery, MD, K. Baker, PhD, J. F. Gusella, PhD, S. J. Fink, MD PhD, R. H. Myers, PhD and A. Herbert, MD PhD

From the Department of Neurology (Drs. Karamohamed, DeStefano, Wilk, Saint-Hilaire, Feldman, Lew, Fink, Myers, and Herbert, and C.M. Shoemaker, K.M. Sullivan, and G. Xu), Boston University School of Medicine, MA; Department of Neurology (Drs. Golbe, Mark, and Lazzarini), University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School, New Brunswick; Departments of Clinical Neurosciences and Medical Genetics (Dr. Suchowersky and N. Labelle), University of Calgary, Alberta, Canada; Division of Neurology, Department of Medicine (Dr. Guttman), University of Toronto, Canada; Department of Neurology (Drs. Currie and Wooten), University of Virginia Health System, Charlottesville; Department of Neurology (Dr. Stacy), Barrow Clinic, Phoenix, AZ; Department of Neurology (Dr. Watts), Emory University, Atlanta, GA; Department of Neurology (Dr. Growdon) and Molecular Neurogenetics Unit (Dr. Gusella), Massachusetts General Hospital, Harvard Medical School, Boston; Department of Neurology (Dr. Lew and Waters), University of Southern California, Los Angeles; Department of Neurology (Drs. Vieregge and Klein), Medical University of Lübeck, Germany; Department of Neurology (Dr. Pramstaller), General Regional Hospital Bolzano, Italy; Department of Neurology (Drs. Racette, Perlmutter, and Parsian), Washington University School of Medicine, Saint Louis, MO; Department of Molecular and Cellular Biology (Dr. Parsian), University of Louisville Health Sciences Center, KY; Department of Neurology (Dr. Singer), University of Miami, FL; and Departments of Neurology and Neuroscience (Drs. Montgomery and Baker), Cleveland Clinic Foundation, OH.

Address correspondence and reprint requests to Dr. Samer Karamohamed, Department of Neurology, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118; e-mail: samer{at}bu.edu

Objective: To identify a haplotype influencing onset age for Parkinson’s disease (PD) in the PARK3 region on chromosome 2p13.

Methods: Single nucleotide polymorphisms (SNP) spanning 2.2 Mb and located in or near potential candidate genes were used to fine map the PARK3 region in 527 patients with familial PD, from 264 families.

Results: TT homozygotes for rs1876487 (G/T) had a 7.4-year younger mean age at onset (p = 0.005) compared to patients with GT and GG genotypes. Furthermore, SNP flanking the sepiapterin reductase (7,8-dihydrobiopterin: NADP+ oxidoreductase) (SPR) gene, rs1876487 (p = 0.02) and rs1150500 (p = 0.04), were associated with younger onset age among persons who did not carry the 174 allele of D2S1394. The SPR gene is implicated in dopamine synthesis. Haplotype analysis of three SNP—rs2421095, rs1876487, rs1561244—revealed an association with onset age (p = 0.023) and a haplotype of A-T-G alleles was associated with younger onset for PD (p = 0.005).

Conclusions: A haplotype at the PARK3 locus, harboring the SPR gene, is associated with onset age of PD. This may suggest a role for the SPR gene in modifying the age at onset of PD.

Received December 20, 2002. Accepted in final form August 13, 2003.

Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the December 9 issue to find the title link for this article.




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