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

Abstract

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 singlenucleotide 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-C-C 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 modifier gene for AAO of PD.

Epidemiology and etiology of Parkinson’s disease: a review of the evidence

“…The PARK10 locus was also linked to age at onset for PD in a US sample [248]. Association between SNPs in the candidate gene ELAVL4 and age at onset for PD or susceptibility to PD were reported in Caucasian populations [249][250][251], but have not been confirmed in other populations.…”

The human RBPome: From genes and proteins to human disease

“…For example, genes like ELAV1, which regulate mRNA stability are known to contribute to breast cancer [65], RBM5, a tumor suppressor gene is known to control cell growth in lung cancer [66], UPF1, subunit of the post splicing multi protein complex is shown to be dysregulated in prostate cancer [67]. RBPs that are known to be dysregulated in neurodegenerative diseases include members of the NOVA family [68], QKI, a candidate gene for schizophrenia [69] and ELAVL4, an important player in parkinson's disease [70]. In addition to these disorders, RBPs were enriched in various inflammatory diseases such as neuronitis, prostatitis, esophagitis suggesting an important role for RBPs in mediating inflammatory responses.…”

Replication of association between ELAVL4 and Parkinson disease: the GenePD study

“…Tag SNPs with minor allele frequency >0.05 were selected to cover the region where previous association had been observed (Noureddine et al 2005). Tag SNPs were replaced by previously published SNPs when there was substantial linkage disequilibrium between the Tag SNP and previously published SNP.…”

“…Meta analysis of previously published results (Haugarvoll et al 2007;Noureddine et al 2005) and the current study examining SNP rs967582 and PD affection status was performed by combining P values as implemented in the program Metal (http://www.sph.umich.edu/csg/abecasis/metal/). Specifically, for each SNP a Z statistic was computed for each study based on the study specific P value and direction of the estimated effect.…”

“…Follow-up studies in the US and Australian cohorts revealed evidence of association between single nucleotide polymorphism (SNP) markers in ELAVL4 and age at onset of PD (Noureddine et al 2005). Subsequent examination in distinct cohorts identified association between ELAVL4 and risk for PD in an Irish case-control cohort, but not in Norwegian or US samples (Haugarvoll et al 2007).…”