Alternative titles; symbols
ORPHA: 2828;
Cytogenetic location: 1p32 Genomic coordinates (GRCh38) : 1:50,200,001-60,800,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p32 | {Parkinson disease 10} | 606852 | 2 |
For a phenotypic description and a discussion of genetic heterogeneity of Parkinson disease (PD), see 168600.
Li et al. (2002) performed a genomic screen for age at onset (AAO) of Parkinson disease (168600), studying 174 families. Heritabilities between 40% and 60% were found. Significant evidence was found for linkage of AAO in Parkinson disease on 1p (lod = 3.41).
Using 781 microsatellite markers, Hicks et al. (2002) performed a genomewide scan on 117 Icelandic patients with classic late-onset Parkinson disease (mean age of onset 65.8 years) and 168 of their unaffected relatives from 51 families. They found linkage to chromosome 1p32, and further analysis yielded a lod score of 4.9 near marker D1S2652 within a 7.6-cM segment. The authors designated this locus PARK10.
By SNP analysis of 267 families with PD, 83 of whom were positively linked to chromosome 1p, Oliveira et al. (2005) identified 2 genes that were significantly associated with age at disease onset: EIF2B3 (606273) and USP24 (610569). P values for SNPs within these genes ranged from 0.007 to 0.0003 depending on the analysis used, with EIF2B showing stronger results. In addition, several SNPs in the HIVEP3 gene (606649) were associated with risk of development of PD (p = 0.002).
Maraganore et al. (2005) performed a 2-tiered, genomewide association study of PD including 443 sib pairs discordant for PD and 332 case-unrelated control pairs. Among 11 SNPs that were borderline significant in both tiers (p less than 0.05), 2 SNPs (rs682705 and rs7520966) tagged the PARK10 locus and were located within the CDCP2 gene (612320). These SNPs yielded significant association with PD (p values of 9.07 x 10(-6) and 2.96 x 10(-5) with odds ratios of 0.66 and 0.67, respectively).
Farrer et al. (2006) found no association between PD and SNPs in the CDCP2 gene among a total of 1,570 patients from 3 cohorts of Norwegian, Irish, and American populations. Farrer et al. (2006) stated that the findings of Maraganore et al. (2005) may be spurious. Goris et al. (2006) also found no association between PD and any of the candidate SNPs identified by Maraganore et al. (2005) among 538 patients with PD.
By examining CDCP2 SNPs in an expanded PD family dataset (293 multiplex and 467 singleton families) and a discordant sib-pair dataset, Li et al. (2007) found no significant association of CDCP2 with PD. They noted that the results confirmed previous negative findings for CDCP2 as a candidate PARK10 gene.
By SNP analysis of 266 multiplex PD families with additional genotyping in 377 singleton PD families, Noureddine et al. (2005) found a significant association between AAO in PD and 2 SNPs in the ELAVL4 gene (168360) on chromosome 1p34: rs967582 and rs2494876 (p = 0.006 and p = 0.035, respectively, after Bonferroni correction). Several haplotypes defined by these and additional SNPs in the gene were also found to be associated with AAO. Noureddine et al. (2005) concluded that there may be a potential role for ELAVL4 as a modifier gene for AAO of PD.
Haugarvoll et al. (2007) observed a significant association between susceptibility to PD and 2 SNPs in the ELAVL4 gene (rs967582 and rs3902720) among 372 Irish patients with PD. However, the data did not show an association with age at onset in this group. There was also no association between AAO or susceptibility to PD in cohorts of patients from Norway or the United States. Haugarvoll et al. (2007) suggested that the findings among the Irish may be due to a Scandinavian/Celtic founder effect.
Among 712 Caucasian PD patients and 312 controls, DeStefano et al. (2008) found that the minor C allele of rs967582 in the ELAVL4 gene was associated with increased risk of PD, yielding an odds ratio of 1.46 and p value of 0.011. However, the p value became 0.0999 after conservative Bonferroni correction. No association was observed for age at onset.
Haugarvoll et al. (2009) genotyped SNPs across the PARK10 locus in 180 PD patients and 180 controls from central Norway, followed by candidate SNP genotyping of 186 PD patients and 186 controls from Ireland, and further SNP analysis of an extended series comprising 530 Norwegian PD patients and 1,142 controls, and 221 Irish and US PD patients and 221 controls. After correction for multiple testing, an association was found between PD and markers within the USP24 gene (combined OR of 0.78, p = 0.0007 at rs13312; OR of 0.80, p = 0.0013 at rs487230). Independently, the association for rs13312 was strongest in the extended Norwegian series (OR 0.76, p = 0.005), although this was not significant after correction for multiple testing. No marker showed consistent association with age at onset. The data suggested that genetic variability in USP24 may be associated with PD. No significant association was observed with SNPs in the HIVEP3, EIF2B3, or ELAVL4 genes.
Wan et al. (2014) concluded that common variation in the PARK10 region on chromosome 1p32 is not associated with risk of Parkinson disease. Analysis of data from a large GWA study of 2,000 cases and 1,986 controls yielded data suggestive of an association with SNPs in the DAB1 gene (603448), but these results were not validated in a replication stage involving a total of 2,113 cases and 2,095 controls. In addition, metaanalyses across all datasets did not identify any genes within the PARK10 locus that showed association with disease susceptibility.
DeStefano, A.L., Latourelle, J., Lew, M. F., Suchowersky, O., Klein, C., Golbe, L. I., Mark, M. H., Growdon, J. H., Wooten, G. F., Watts, R., Guttman, M., Racette, B. A., and 35 others. Replication of association between ELAVL4 and Parkinson disease: the GenePD study. Hum. Genet. 124: 95-99, 2008. [PubMed: 18587682] [Full Text: https://doi.org/10.1007/s00439-008-0526-4]
Farrer, M. J., Haugarvoll, K., Ross, O. A., Stone, J. T., Milkovic, N. M., Cobb, S. A., Whittle, A. J., Lincoln, S. J., Hulihan, M. M., Heckman, M. G., White, L. R., Aasly, J. O., Gibson, J. M., Gosal, D., Lynch, T., Wszolek, Z. K., Uitti, R. J., Toft, M. Genomewide association, Parkinson disease, and PARK10. (Letter) Am. J. Hum. Genet. 78: 1084-1088, 2006. [PubMed: 16685661] [Full Text: https://doi.org/10.1086/504728]
Goris, A., Williams-Gray, C. H., Foltynie, T., Compston, D. A. S., Barker, R. A., Sawcer, S. J. No evidence for association with Parkinson disease for 13 single-nucleotide polymorphisms identified by whole-genome association screening. (Letter) Am. J. Hum. Genet. 78: 1088-1090, 2006. [PubMed: 16685662] [Full Text: https://doi.org/10.1086/504726]
Haugarvoll, K., Toft, M., Ross, O. A., Stone, J. T., Heckaman, M. F., White, L. R., Lynch, T., Gibson, J. M., Wszolek, Z. K., Uitti, R. J., Aasly, J. O., Farrer, M. J. ELAVL4, PARK10, and the Celts. Mov. Disord. 22: 585-587, 2007. [PubMed: 17230446] [Full Text: https://doi.org/10.1002/mds.21336]
Haugarvoll, K., Toft, M., Skipper, L., Heckman, M. G., Crook, J. E., Soto, A., Ross, O. A., Hulihan, M. M., Kachergus, J. M., Sando, S. B., White, L. R., Lynch, T., Gibson, J. M., Uitti, R. J., Wszolek, Z. K., Aasly, J. O., Farrer, M. J. Fine-mapping and candidate gene investigation within the PARK10 locus. Europ. J. Hum. Genet. 17: 336-343, 2009. [PubMed: 18854859] [Full Text: https://doi.org/10.1038/ejhg.2008.187]
Hicks, A. A., Petursson, H., Jonsson, T., Stefansson, H., Johannsdottir, H. S., Sainz, J., Frigge, M. L., Kong, A., Gulcher, J. R., Stefansson, K., Sveinbjornsdottir, S. A susceptibility gene for late-onset idiopathic Parkinson's disease. Ann. Neurol. 52: 549-555, 2002. [PubMed: 12402251] [Full Text: https://doi.org/10.1002/ana.10324]
Li, Y.-J., Scott, W. K., Hedges, D. J., Zhang, F., Gaskell, P. C., Nance, M. A., Watts, R. L., Hubble, J. P., Koller, W. C., Pahwa, R., Stern, M. B., Hiner, B. C., and 20 others. Age at onset in two common neurodegenerative diseases is genetically controlled. Am. J. Hum. Genet. 70: 985-993, 2002. [PubMed: 11875758] [Full Text: https://doi.org/10.1086/339815]
Li, Y. J., Deng, J., Mayhew, G. M., Grimsley, J. W., Huo, X., Vance, J. M. Investigation of the PARK10 gene in Parkinson disease. Ann. Hum. Genet. 71: 639-647, 2007. [PubMed: 17388942] [Full Text: https://doi.org/10.1111/j.1469-1809.2007.00353.x]
Maraganore, D. M., de Andrade, M., Lesnick, T. G., Strain, K. J., Farrer, M. J., Rocca, W. A., Pant, P. V. K., Frazer, K. A., Cox, D. R., Ballinger, D. G. High-resolution whole-genome association study of Parkinson disease. Am. J. Hum. Genet. 77: 685-693, 2005. [PubMed: 16252231] [Full Text: https://doi.org/10.1086/496902]
Noureddine, M. A., Qin, X.-J., Oliveira, S. A., Skelly, T. J., van der Walt, J., Hauser, M. A., Pericak-Vance, M. A., Vance, J. M., Li, Y.-J. Association between the neuron-specific RNA-binding protein ELAVL4 and Parkinson disease. Hum. Genet. 117: 27-33, 2005. [PubMed: 15827745] [Full Text: https://doi.org/10.1007/s00439-005-1259-2]
Oliveira, S. A., Li, Y.-J., Noureddine, M. A., Zuchner, S., Qin, X., Pericak-Vance, M. A., Vance, J. M. Identification of risk and age-at-onset genes on chromosome 1p in Parkinson disease. Am. J. Hum. Genet. 77: 252-264, 2005. [PubMed: 15986317] [Full Text: https://doi.org/10.1086/432588]
Wan, J. Y., Edwards, K. L., Hutter, C. M., Mata, I. F., Samii, A., Roberts, J. W., Agarwal, P., Checkoway, H., Farin, F. M., Yearout, D., Zabetian, C. P. Association mapping of the PARK10 region for Parkinson's disease susceptibility genes. Parkinsonism Relat. Disord. 20: 93-98, 2014. [PubMed: 24156912] [Full Text: https://doi.org/10.1016/j.parkreldis.2013.10.001]