title: Is Parkinson disease associated with lysosomal integral membrane protein type-2?: challenges in interpreting association data.
abstract: Several genetic risk factors have been identified for Parkinson disease (PD), including mutations in glucocerebrosidase (GBA1). Recently, two single nucleotide polymorphisms (SNPs) described as SCARB2 SNPs were reported to be associated with PD. SCARB2 is an attractive candidate gene for PD as it encodes for lysosomal integral membrane protein type 2 (LIMP-2), a protein involved in transporting glucocerebrosidase from the ER to the lysosome. The first SNP, rs6812193, located 64 kb upstream of SCARB2, was identified in a Parkinson disease Genome Wide Association study of Americans with European ancestry (p = 7.6 × 10(-10), OR = 0.84), but was not replicated in a study in the Han Chinese. The second SNP, rs6825004, located within intron 2 of SCARB2 was reported in an association study of Parkinson disease in Greece (p = 0.02, OR = 0.68). We explored whether the two SNPs impact SCARB2 expression or LIMP-2 protein levels, testing fifteen control samples. First, the genotypes for each subject were determined for both SNPs using a Taqman assay. Then, RNA and protein were extracted from the corresponding cell pellets. Neither the relative RNA expression by real-time PCR, nor LIMP-2 levels on Western blots correlated with SNP genotype. Thus, these two reported SNPs may not be related to SCARB2 and demonstrate the challenges in interpreting some association studies. While LIMP-2 could still play a role in PD pathogenesis, this study does not provide evidence that the SNPs identified are in fact related to LIMP-2.
authors: Section on Molecular Neurogenetics, Medical Genetics Branch, NHGRI, NIH, Bethesda, MD 20892, USA.
authors: Emerson
authors: E
authors: Maniwang
authors: Nahid
authors: N
authors: Tayebi
authors: Ellen
authors: E
authors: Sidransky
mesh_terms: D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D005962:Glucosylceramidase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051907:Lysosomal Membrane Proteins / Q000145:classification / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D051116:Receptors, Scavenger / Q000235:genetics*; D012307:Risk Factors
chemical_list: D051907:Lysosomal Membrane Proteins; D051116:Receptors, Scavenger; C074299:SCARB2 protein, human; D005962:Glucosylceramidase