Association study of essential tremor genetic loci in Parkinson's disease.

A recent genome-wide association study identified variants associated with essential tremor (ET). The present study aimed to examine potential genetic overlap between ET and Parkinson's disease (PD). The top 22 variants identified by the ET genome-wide association study and 4 additional variants from previous studies were genotyped in a cohort of French and French-Canadian PD patients (n = 717) and controls (n = 595). Logistic regression analysis, adjusted for age and sex, was used to test for association between genotype and PD. None of the variants tested in the present study was significantly associated with PD. Our results do not support a role of ET-associated genetic variants in PD.

SCARB2 variants and glucocerebrosidase activity in Parkinson's disease.

Mutations in glucocerebrosidase (GBA) are a common risk factor for Parkinson's disease (PD). The scavenger receptor class B member 2 (SCARB2) gene encodes a receptor responsible for the transport of glucocerebrosidase (GCase) to the lysosome. Two common SNPs in linkage disequilibrium with SCARB2, rs6812193 and rs6825004, have been associated with PD and Lewy Body Disease in genome wide association studies. Whether these SNPs are associated with altered glucocerebrosidase enzymatic activity is unknown. Our objective was to determine whether SCARB2 SNPs are associated with PD and with reduced GCase activity. The GBA gene was fully sequenced, and the LRRK2 G2019S and SCARB2 rs6812193 and rs6825004 SNPs were genotyped in 548 PD patients and 272 controls. GCase activity in dried blood spots was measured by tandem mass spectrometry. We tested the association between SCARB2 genotypes and PD risk in regression models adjusted for gender, age, and LRRK2 G2019S and GBA mutation status. We compared GCase activity between participants with different genotypes at rs6812193 and rs6825004. Genotype at rs6812193 was associated with PD status. PD cases were less likely to carry the T allele than the C allele (OR=0.71; p=0.004), but GCase enzymatic activity was similar across rs6812193 genotypes (C/C: 11.88 µmol/l/h; C/T: 11.80 µmol/l/h; T/T: 12.02 µmol/l/h; p=0.867). Genotype at rs6825004 was not associated with either PD status or GCase activity. In conclusion, our results support an association between SCARB2 genotype at rs6812193 and PD, but suggest that the increased risk is not mediated by GCase activity.

Case-Control and Family-Based Association Study of Specific PTPRD Variants in Restless Legs Syndrome.

BACKGROUND: The exact genetic causes within each of the known restless legs syndrome (RLS) loci are still unknown. Recently, it was suggested that an intronic protein tyrosine phosphatase, receptor type δ (PTPRD) single-nucleotide polymorphism (SNP) (reference SNP no. rs2381970) is associated with its expression, which may lead to RLS and other related phenotypes. Another study identified 3 nonsynonymous PTPRD variants in familial RLS cases: p.Q447E (a residue change from glutamine to glutamic acid at position 447), p.T781A (a residue change from threonine to alanine at position 781), and p.R995C (a residue change from arginine to cysteine at position 995). METHODS: Two cohorts of sporadic RLS, a French-Canadian cohort and a cohort from the United States, with a total of 577 patients and 455 controls, and an additional familial RLS cohort with a total of 635 individuals (140 families) were genotyped for these 4 variants (rs2381970, p.Q447E, p.T781A, and p.R995C) by using specific TaqMan probes, and the effects of each variant as well as haplotypes were analyzed. RESULTS: None of the 4 PTPRD-specific variants or haplotypes that were tested were associated with RLS in the case-control cohorts or in the familial cohort. The frequencies of the rs2381970 variant in the French-Canadian and US cohorts were 0.07 and 0.04, respectively, and their frequencies in the respective control populations were 0.06 and 0.04, respectively (P > 0.4 for both). Similar results were obtained for the 3 nonsynonymous variants. CONCLUSIONS: Although the PTPRD gene is well established as an RLS-associated locus, the rs2381970 SNP and the 3 nonsynonymous PTPRD variants are not likely to cause or affect the risk for developing RLS in the study population. More studies in other populations are needed to determine their potential role in RLS.

Analysis of functional GLO1 variants in the BTBD9 locus and restless legs syndrome.

BACKGROUND: Restless legs syndrome (RLS) is a common disorder, with several known genetic risk factors, yet the actual genetic causes are unclear. METHODS: Whole-exome sequencing (WES) was performed in seven RLS families, focusing on six known genetic loci: MEIS1, BTBD9, PTPRD, MAP2K5/SKOR1, TOX3, and rs6747972. Genotyping using specific TaqMan assays was performed in two case-control cohorts (627 patients and 410 controls), and in a familial cohort (n = 718). RESULTS: WES identified two candidate GLO1 variants (within the BTBD9 locus), p.E111A and the promoter variant c.-7C>T, both co-segregated with the disease in four families. The GLO1 p.E111A variant was associated with RLS in the French-Canadian cohort (odds ratio, OR = 1.38, p = 0.02), and demonstrated a similar trend in the US cohort (OR = 1.26, p = 0.09, combined analysis OR = 1.28, p = 0.009). However, the original genome-wide association study (GWAS) marker, BTBD9 rs9357271, had stronger association with RLS (OR = 1.84, p = 0.0003). Conditional haplotype analysis, controlling for the effect of the BTBD9 variant rs9357271, demonstrated that the association of GLO1 p.E111A turned insignificant (p = 0.54). In the familial cohort, the two GLO1 variants were not associated with RLS. Other variants in the SKOR1 (p.W200R and p.A672V) and PTPRD (p.R995C, p.Q447E, p.T781A, p.Q447E, and c.551-4C > G) genes, did not co-segregate with the disease. CONCLUSIONS: The GLO1 variations studied here are not the source of association of the BTBD9 locus with RLS. It is likely that the genetic variants affecting RLS susceptibility are located in regulatory regions.

Novel VPS13B Mutations in Three Large Pakistani Cohen Syndrome Families Suggests a Baloch Variant with Autistic-Like Features.

BACKGROUND: Cohen Syndrome (COH1) is a rare autosomal recessive disorder, principally identified by ocular, neural and muscular deficits. We identified three large consanguineous Pakistani families with intellectual disability and in some cases with autistic traits. METHODS: Clinical assessments were performed in order to allow comparison of clinical features with other VPS13B mutations. Homozygosity mapping followed by whole exome sequencing and Sanger sequencing strategies were used to identify disease-related mutations. RESULTS: We identified two novel homozygous deletion mutations in VPS13B, firstly a 1 bp deletion, NM_017890.4:c.6879delT; p.Phe2293Leufs*24, and secondly a deletion of exons 37-40, which co-segregate with affected status. In addition to COH1-related traits, autistic features were reported in a number of family members, contrasting with the "friendly" demeanour often associated with COH1. The c.6879delT mutation is present in two families from different regions of the country, but both from the Baloch sub-ethnic group, and with a shared haplotype, indicating a founder effect among the Baloch population. CONCLUSION: We suspect that the c.6879delT mutation may be a common cause of COH1 and similar phenotypes among the Baloch population. Additionally, most of the individuals with the c.6879delT mutation in these two families also present with autistic like traits, and suggests that this variant may lead to a distinct autistic-like COH1 subgroup.

Genetic markers of Restless Legs Syndrome in Parkinson disease.

INTRODUCTION: Several studies proposed that Restless Legs Syndrome (RLS) and Parkinson disease (PD) may be clinically and/or etiologically related. To examine this hypothesis, we aimed to determine whether the known RLS genetic markers may be associated with PD risk, as well as with PD subtype. METHODS: Two case-control cohorts from Tel-Aviv and New-York, including 1133 PD patients and 867 controls were genotyped for four RLS-related SNPs in the genes MEIS1, BTBD9, PTPRD and MAP2K5/SKOR1. The association between genotype, PD risk and phenotype was tested using multivariate regression models. RESULTS: None of the tested SNPs was significantly associated with PD risk, neither in any individual cohort nor in the combined analysis after correction for multiple comparisons. The MAP2K5/SKOR1 marker rs12593813 was associated with higher frequency of tremor in the Tel-Aviv cohort (61.0% vs. 46.5%, p = 0.001, dominant model). However, the risk allele for tremor in this gene has been associated with reduced RLS risk. Moreover, this association did not replicate in Tremor-dominant PD patients from New-York. CONCLUSION: RLS genetic risk markers are not associated with increased PD risk or subtype in the current study. Together with previous genetic, neuropathological and epidemiologic studies, our results further strengthen the notion that RLS and PD are likely to be distinct entities.