Glucocerebrosidase Gene L444P mutation is a risk factor for Parkinson's disease in Chinese population

Abstract

An association between mutations in the glucocerebrosidase (GBA) gene and Parkinson's disease (PD) has been reported in several populations. We searched for four common GBA mutations (L444P, F213I, R353W, and N370S) in 402 Chinese PD patients and 413 age- and sex-matched controls. In the PD cohort, 11 patients were found carrying a heterozygous GBA mutation and all of them had the L444P mutation. Heterozygous GBA mutations were detected none in controls. The GBA gene L444P mutation was detected at a significantly higher frequency among PD patients (11/402 = 2.74%), when compared with the control group (0/413): P = 0.0007. To evaluate the possible role of the GBA gene L444P mutation in PD in Ashkenazi Jewish and non-Jewish populations, we conducted a meta-analysis on the topic. In the Chinese population, the GBA gene L444P mutation was detected at a significantly higher frequency among PD patients, when compared with the control group: Z = 3.83, P = 0.0001, OR = 8.42, confidence interval = 95%, 2.83-25.06. In the non-Jewish populations, the difference was obviously significant: Z = 5.76, P < 0.00001, OR = 8.82, confidence interval = 95%, 4.21-18.48. The results suggest that the GBA gene L444P mutation appears to be a risk factor for PD in Chinese population.

Polygenic determinants of Parkinson's disease in a Chinese population

“…In our previous study, we have replicated 3 GBA gene mutations in our population and proved that the L444P mutation in GBA gene appears to be a risk factor for PD in our population (Sun et al, 2010). We proved this association again with larger sample with p ¼ 0.001, OR ¼ 27.114, 95% CI ¼ 3.668e200.455.…”

“…To our knowledge, it is the most comprehensive genetic association study of candidate genes in Chinese ethnicity subjects with PD to date. Polymorphic variants in SNCA and LRRK2 genes and heterozygous mutations in the GBA gene, however, have been validated as genetic susceptibility factors (Mueller et al, 2005;Ross et al, 2011;Satake et al, 2009;Sidransky et al, 2009;Simón-Sánchez et al, 2009;Sun et al, 2010;Tan et al, 2010aTan et al, , 2010b. GWASs for PD have linked the 2 well-known loci (MAPT and SNCA) to the risk of PD, and a few novel loci are also revealed, such as PARK16, GAK, HLA-DR, BST1, and so on (Edwards et al, 2010;Pankratz et al, 2010;Saad et al, 2011;Satake et al, 2009;Simón-Sánchez et al, 2009;UK Parkinson's Disease Consortium et al, 2011).…”

“…It has been reported that some polymorphisms are associated with the risk of PD, such as Rep1, rs356165, and rs11931074 in SNCA gene (Mueller et al, 2005;Satake et al, 2009;Simón-Sánchez et al, 2009;Tan et al, 2010a); G2385R and R1628P in LRRK2 gene Tan et al, 2010aTan et al, , 2010b; rs242562 and rs2435207 in MAPT gene (Skipper et al, 2004;Vandrovcova et al, 2009); and L444P in GBA gene (Sidransky et al, 2009;Sun et al, 2010). More recently, genomewide association studies (GWASs) of complex diseases have identified sequence variants that are consistently associated with the risk of such diseases.…”

“…In this study, we investigated whether independent and joint effects of variants in the previously mentioned 8 genes and/or loci will contribute to PD in a Chinese cohort consisting of 1061 well-characterized PD patients and 1066 control subjects from Central South of Mainland China. Because PARK16 and L444P in GBA gene were reported associating with the risk of Asian PD (Satake et al, 2009;Sidransky et al, 2009;Sun et al, 2010), we also analyzed the 2 loci in this study.…”

The p.L302P mutation in the lysosomal enzyme gene SMPD1 is a risk factor for Parkinson disease

“…Founder mutations in GBA can be detected in 1 out of 16 Ashkenazi Jews, and were shown to be important risk factors for Parkinson disease (PD) in this population 2,3 and in many other populations worldwide. [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] Three other lysosomal storage diseases that are caused by founder mutations can be found in the AJ population: Tay-Sachs disease 19 (carrier frequency of 1:27 20 ), Niemann-Pick disease type A 21 (1:115 20 ), and mucolipidosis type IV 22 (1:89 20 ). These 3 autosomal recessive diseases are caused by mutations in genes encoding lysosomal enzymes, 23 and their deficiency results in cellular accumulation of the enzymes' substrates.…”