New Genetic Risk Factors for Parkinson's Identified

Megan Brooks

July 28, 2014

An international team of scientists has identified 6 new genetic risk factors for Parkinson's disease (PD).

"Unraveling the genetic underpinnings of Parkinson's is vital to understanding the multiple mechanisms involved in this complex disease, and hopefully, may one day lead to effective therapies," senior investigator Andrew Singleton, PhD, from the National Institute on Aging, said in a news release from the National Institutes of Health (NIH) announcing the discovery.

The investigators conducted a large-scale meta-analysis of PD genome-wide association studies (GWAS) using a common set of nearly 7.9 million variants across 13,708 PD cases and 95,282 controls, all of European ancestry.

They identified 26 loci significantly associated with PD, according to a report online July 27 in Nature Genetics. They tested these 26 loci and 6 other previously reported loci in an independent set of 5353 PD cases and 5551 controls.

Substantial Cumulative Risk

Using the NeuroX gene chip that contains roughly 24,000 common gene variants thought to be associated with various neurodegenerative disorders, they confirmed 24 of the 32 single nucleotide polymorphisms (SNPs) tested as genetic risk factors for PD, including 6 newly identified risk loci (SIPA1L2, INPP5F, MIR4697, GCH1, VPS13C, and DDRGK1).

Conditional analyses within loci identified 4 loci contain a secondary independent risk variant, they report. Altogether, the investigators identified and replicated 28 independent risk variants for PD across 24 loci.

Although the effect of each individual locus was "small," risk profile analysis showed "substantial cumulative risk" in comparing the highest and lowest quintiles of genetic risk (odds ratio [OR], 3.31; 95% confidence interval [CI], 2.55 – 4.30), the investigators say.

Some of the newly identified risk loci are thought to be involved with Gaucher's disease, and in regulating inflammation and dopamine as well as α-synuclein, a protein that accumulates in the brains of some patients with PD, the NIH news release notes. The investigators say further research is needed to determine the roles of the variants identified in this study.

"The study brought together a large international group of investigators from both public and private institutions who were interested in sharing data to accelerate the discovery of genetic risk factors for Parkinson's disease," Margaret Sutherland, PhD, a program director at the National Institute of Neurological Disorders and Stroke, said in the news release.

"The advantage of this collaborative approach is highlighted in the identification of pathways and gene networks that may significantly increase our understanding of Parkinson's disease," she added.

Dr. Sutherland said the study also demonstrates the utility of the NeuroX chip for "unlocking the secrets of neurodegenerative disorders. The power of these high-tech, data-driven genomic methods allows scientists to find the needle in the haystack that may ultimately lead to new treatments."

The study was supported by National Institute on Aging Intramural Research Program and grants from the National Institute of Neurological Disorders and Stroke, the National Institute on Aging, and the National Institute of Environmental Health Sciences. The authors have disclosed no relevant financial relationships.

Nature Gen. Published online July 27, 2014. Abstract


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