Association between the neuron-specific RNA-binding protein ELAVL4 and Parkinson disease

Inflammatory processes have been implicated in the cascade of events that lead to nerve cell death. In the nervous system, a number of genes involved in inflammation pathways are regulated post-transcriptionally via the interaction of their mRNAs with specific RNA-binding Hu proteins, the vertebrate homologues of the Drosophila ELAV ( for embryonic lethal abnormal vision). The gene encoding ELAVL4, a member of the Hu family of proteins, is located 2 Mb from the chromosome 1p linkage region peak for age-at-onset (AAO) of Parkinson disease (PD) ( LOD = 3.41). Nine single-nucleotide polymorphisms ( SNPs) in ELAVL4 were genotyped for 266 multiplex families ( 1,223 samples). Additional genotyping in 377 singleton families was performed for a subset of five SNPs ( SNPs 1 - 5) that were not in linkage disequilibrium. SNP 2 ( located in the first intron of ELAVL4) showed a strong significant association with AAO of PD ( P = 0.006), and SNP 5 ( a coding SNP in ELAVL4) showed a moderately significant association ( P = 0.035). Haplotype analysis revealed that the A-C haplotype at SNPs 2 and 3 has the strongest significant association with AAO ( P = 0.0001) among all combinations of two or three loci. The A-C haplotype remained significant for AAO after the inclusion of the C allele at SNP 5 to this haplotype (A-CC haplotype, P=0.00018). Although SNP 5 was found to associate with PD risk in the early-onset subset of PD families ( at least one affected with AAO < 40 years, 60 families), we believe that it is a by-product of its association with AAO. Taken together, these results suggest a potential role for ELAVL4 as a modi. er gene for AAO of PD.