Berta C. Leis

Glucocerebrosidase Gene Mutations: A Risk Factor for Lewy Body Disorders

BACKGROUND Mutations in the glucocerebrosidase (GBA) gene have been reported to modify risk for Parkinson disease (PD) and dementia with Lewy bodies (DLB). However, these findings have not been consistently replicated, and most studies have had substantial methodological shortcomings. OBJECTIVE To better assess the role of GBA variants in altering risk for Lewy body disorders. DESIGN Case-control study. SETTING Four movement disorder clinics in the Seattle, Washington, area. PARTICIPANTS Seven hundred twenty-one patients with PD, 554 healthy control subjects, and 57 patients with DLB. MAIN OUTCOME MEASURES Disease status and presence or absence of the 2 most common GBA mutations (N370S and L444P). RESULTS We observed a significantly higher heterozygote frequency for the 2 mutations in patients with PD (2.9%; P <.001) and those with DLB (3.5%; P = .045) compared with control subjects (0.4%). CONCLUSION Our findings suggest that GBA mutations exert a large effect on susceptibility for Lewy body disorders at the individual level but are associated with a modest (approximately 3%) population-attributable risk in individuals of European ancestry.

Combined Effects of Smoking, Coffee, and NSAIDs on Parkinson's Disease Risk

Inverse associations of Parkinsons disease (PD) with cigarette smoking, coffee drinking, and nonsteroidal anti‐inflammatory drug (NSAID) use have been reported individually, but their joint effects have not been examined. To quantify associations with PD for the individual, two‐way and three‐way combinations of these factors, a case–control association study with 1,186 PD patients and 928 controls was conducted. The study setting was the NeuroGenetics Research Consortium. Subjects completed a structured questionnaire regarding smoking, coffee, and NSAID consumption. Odds ratios were calculated using unconditional logistic regression. Smoking, coffee, and over the counter NSAID use as individual factors exhibited significantly reduced risks of 20% to 30%. The two‐way and three‐way combinations were associated with risk reduction of 37% to 49%, and 62%, respectively. Smoking and coffee exhibited significant inverse risk trends with increasing cumulative exposures, suggesting dose–response relations. With respect to the combination of all three exposures, persons who were at the highest exposure strata for smoking and coffee and used NSAIDs had an estimated 87% reduction in risk (OR = 0.13, 95% CI = 0.06–0.29). Whether this finding reflects true biologic protection needs to be investigated.

Association analysis of MAPT H1 haplotype and subhaplotypes in Parkinson's disease.

An inversion polymorphism of approximately 900kb on chromosome 17q21, which includes the microtubule‐associated protein tau (MAPT) gene defines two haplotype clades, H1 and H2. Several small case–control studies have observed a marginally significant excess of the H1/H1 diplotype among patients with Parkinsons disease (PD), and one reported refining the association to a region spanning exons 1 to 4 of MAPT. We sought to replicate these findings.

LRRK2 G2019S in families with Parkinson disease who originated from Europe and the Middle East: evidence of two distinct founding events beginning two millennia ago.

The leucine-rich repeat kinase 2 (LRRK2) G2019S mutation is the most common genetic determinant of Parkinson disease (PD) identified to date. It accounts for 1%-7% of PD in patients of European origin and 20%-40% in Ashkenazi Jews and North African Arabs with PD. Previous studies concluded that patients from these populations all shared a common Middle Eastern founder who lived in the 13th century. We tested this hypothesis by genotyping 25 microsatellite and single-nucleotide-polymorphism markers in 22 families with G2019S and observed two distinct haplotypes. Haplotype 1 was present in 19 families of Ashkenazi Jewish and European ancestry, whereas haplotype 2 occurred in three European American families. Using a maximum-likelihood method, we estimated that the families with haplotype 1 shared a common ancestor 2,250 (95% confidence interval 1,650-3,120) years ago, whereas those with haplotype 2 appeared to share a more recent founder. Our data suggest two separate founding events for G2019S in these populations, beginning at a time that coincides with the Jewish Diasporas.

Identification and haplotype analysis of LRRK2 G2019S in Japanese patients with Parkinson disease

LRRK2 G2019S is the most common known cause of Parkinson disease (PD) in patients of European origin, but little is known about its distribution in other populations. The authors identified two of 586 Japanese patients with PD heterozygous for the mutation who shared a haplotype distinct from that observed in Europeans. This suggests that G2019S originated from separate founders in Europe and Japan and is more widely dispersed than previously recognized.

Genetic association between α-synuclein and idiopathic parkinson's disease†

Point mutations and copy number variations in SNCA, the gene encoding α‐synuclein, cause familial Parkinsons disease (PD). A dinucleotide polymorphism (REP1) in the SNCA promoter may be a risk factor for common forms of PD. We studied 1,802 PD patients and 2,129 controls from the NeuroGenetics Research Consortium, using uniform, standardized protocols for diagnosis, subject recruitment, data collection, genotyping, and data analysis. Three common REP1 alleles (257, 259, and 261 bp, with control frequencies of 0.28, 0.65, and 0.06) and several rare alleles (combined frequency <0.01) were detected. We confirmed association of REP1 with PD risk [odds ratio (OR) = 0.86, P = 0.006 for 257‐carriers; OR = 1.25, P = 0.022 for 261‐carriers]. Using a normalization procedure, we showed that the 257 and 261 alleles are both independently associated with PD risk (for 257, P = 0.002 in overall data, 0.003 in non‐familial PD, 0.001 in early‐onset PD; for 261, P = 0.056 in overall data, 0.024 in non‐familial PD, 0.052 in early‐onset PD). The 257‐associated risk was consistent with a dominant model [hazard ratio (HR) = 0.99, P = 0.91 for 257/257 vs. 257/X where X denotes all other common alleles; HR = 1.16, P = 0.004 for X/X vs. 257/X]. The 261‐associated risk was consistent with a recessive model (HR = 1.89, P = 0.026 for 261/261 vs. 261/X; HR = 0.95, P = 0.42 for X/X vs. 261/X). Genotype‐specific mean onset ages (±SD) ranged from 54.8 ± 12.1 for 261/261 to 59.4 ± 11.5 for 257/257, displaying a trend of decreasing onset age with increasing allele size (P = 0.055). Genetic variation in SNCA and its regulatory regions play an important role in both familial and sporadic PD.

Lack of evidence for an association between UCHL1 S18Y and Parkinson’s disease

UCHL1 has been proposed as a candidate gene for Parkinson’s disease (PD). A meta‐analysis of white and Asian subjects reported an inverse association between the non‐synonymous UCHL1 S18Y polymorphism and PD risk. However, this finding was not replicated in a large case–control study and updated meta‐analysis restricted to white subjects. We performed a case–control study of 1757 PD patients recruited from movement disorder clinics and 2016 unrelated controls from four regions of the United States. All subjects self‐reported as white. We did not observe evidence for an association between S18Y genotypes and PD (overall P‐value for association: P = 0.42). After adjustment for age, sex, and recruitment region, the odds ratio for Y/S versus S/S was 0.91 (95% CI: 0.78–1.06) and for Y/Y versus S/S was 0.87 (95% CI: 0.58–1.29). We also did not observe a significant association for recessive or dominant models of inheritance, or after stratification by age at onset, age at blood draw, sex, family history of PD, or recruitment region. Our results suggest that UCHL1 S18Y is not a major susceptibility factor for PD in white populations although we cannot exclude the possibility that the S18Y variant exerts weak effects on risk, particularly in early‐onset disease.

DBH -1021C-->T does not modify risk or age at onset in Parkinson's disease.

DBH is a candidate gene in Parkinsons disease (PD) and contains a putative functional polymorphism (‐1021C→T) that has been reported to modify PD susceptibility. We examined −1021C→T in a sample of 1,244 PD patients and 1,186 unrelated control subjects. There was no significant difference in allele (p = 0.14) or genotype (p = 0.26) frequencies between the two groups. A similar result was obtained after pooling our data with those previously published. Furthermore, we found no evidence for an effect of genotype on age at onset among patients. Our findings argue against DBH −1021C→T as a risk factor or age at onset modifier in PD. Ann Neurol 2007