Common Disease, Multiple Rare Variants: Gaucher Mutations in PD (AAN 2008)

Subject: Common Disease, Multiple Rare Variants: Gaucher Mutations in PD (AAN 2008)

Date: 4/20/2008

E-MOVE reports from the Annual Meeting of the American Academy of Neurology, Chicago, April 14-18, 2008. Poster and platform session numbers are from Neurology 2008;70(suppl 1)

Heterozygous rare variants associated with Gaucher disease confer robust susceptibility to Parkinson disease
J Mitsui, I Mizuta, R Atshida, Y Takahasi, J Guto, H Date, I Iwata, M Murata, M Yamamoto, N Hattori, T Toda, S Tsuji
P03.067; A144

Multiple, individually rare mutations in the glucocerebrosidase gene together occur in almost 10% of Parkinson's disease cases in Japan, according to this study.

Complete sequencing of the GBA gene was performed in 534 unrelated PD patients and 545 controls. Mutations were found in 52 (9.8%) PD patients, and 2 (0.4%) controls. A total of 11 different mutations were found. Five mutations affected only 1 patient each. The 2 most common mutations affected 14 and 15 patients each; 1 of these was found in 2 controls.

All identified mutations were also known as disease-causing mutations in Gaucher disease. In contrast, non-Gaucher-associated gene variants were as common in controls as in PD patients. PD patients with mutations were significantly younger than those without.

The authors emphasize "a paradigm shift from the 'common disease--common variants' hypothesis to the 'common disease--multiple rare variants' hypothesis in our search for disease susceptibility genes in sporadic PD, which may be applicable to studies of other diseases....Multiple rare variants can be identified only by extensive resequencing, and are difficult to be detected by association studies employing common SNPs. Our results strongly emphasize the importance of conducting a comprehensive resequencing analysis of candidate genes in detecting even the rarest variants."

Previous E-MOVE reports on the link between GBA and PD are archived HERE
http://www.mdvu.org/emove/article.asp?ID=1022
and HERE
http://www.mdvu.org/emove/article.asp?ID=676