Genetic Risk Factor Tied to Parkinson's Disease

ROCHESTER, Minn., Aug. 9 -- Variability in a single gene may account for 3% of the worldwide risk for Parkinson's disease, an international team reported.

In an world-wide analysis of clinical and genetic data from 2,692 Parkinson's patients and 2,652 matched healthy controls, persons with allele-length variability in the dinucleotide repeat sequence (REP1) of the ?-synuclein gene promoter (SNCA REP1) had an almost 1.5 times greater risk for Parkinson's disease.

This large-scale collaborative analysis demonstrates that the SNCA gene is not only a rare cause of autosomal dominant disease in some families as previously shown, but also a susceptibility gene for Parkinson's at the population level, the researchers said.

The collaborative study, carried out from 2004 to 2005, included individual data from 11 international sites that met stringent criteria for concordance with Hardy-Weinberg equilibrium and a low genotyping error rate, Demetrius Maraganore, M.D., of the Mayo Clinic here and colleagues in 11 countries reported in the Aug. 9 issue of the Journal of the American Medical Association.

"Our findings support the development of therapies that reduce alpha-synuclein gene expression," Dr. Maraganore said. "Such therapies have the potential to prevent or delay the onset of Parkinson's disease or to halt or slow its progression."

Genotyping was performed for SNCA REP1, -770, and -116 markers at individual sites, they said.

Analysis to determine the role of allele-length variability in the dinucleotide repeat sequence (REP1) of the ?-synuclein gene promoter (SNCA REP1) and flanking markers found that the SNCA REP1 alleles differed in frequency for Parkinson's cases and controls (P<0.001), Dr. Maraganore and colleagues said.

Genotypes, defined by the 263 base-pair allele, were associated with Parkinson's disease (odds ratio, 1.43; 95% confidence interval, 1.22-1.69; P<0.001 for trend).

Multilocus haplotypes also differed in frequency for cases and controls (global score statistic, P<0.001). Two-loci haplotypes were associated with Parkinson's only when they included REP1 as one of the loci. However, genotypes defined by REP1 alleles did not modify the age at onset (P=0.55), the researchers said.

Strengths of the study, they said, are that it included published and unpublished data from diverse sites worldwide and that the combined sample size was substantial. "To our knowledge, this represents the largest case-control study of Parkinson's disease to date," they wrote.

Weaknesses included site-specific differences inherent in all collaborative analyses of genetic-association studies.

In conclusion, the researchers said, the additive effect of REP 1 locus variability and other common gene variants may ultimately account for a substantial fraction of the susceptibility to Parkinson's disease.

However, "large-scale collaborations with meticulous standardization of methods (including statistical adjustments for multiple possible confounders) would be desirable. Similarly, large-scale collaborations will be required to document interactions of SNCA with other genes or environmental factors conferring susceptibility to Parkinson's disease," the team concluded.

Dr. Maraganore and the Mayo Clinic reported pending patent applications for a device that treats neurodegenerative diseases. The Mayo Clinic has licensed this technology to Alnylam Pharmaceuticals, and both Mayo Clinic and Dr. Maraganore may receive royalties from that license. Several researchers reported consulting relationships with Pfizer and Amgen for which they have received no compensation.