Genomewide association study for onset age in Parkinson disease

Jeanne C. Latourelle, Nathan Pankratz, Alexandra Dumitriu, Jemma B. Wilk, Stefano Goldwurm, Gianni Pezzoli, Claudio B. Mariani, Anita L. DeStefano, Cheryl Halter, James F. Gusella, William C. Nichols, Richard H. Myers, Tatiana Foroud

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Abstract

Background: Age at onset in Parkinson disease (PD) is a highly heritable quantitative trait for which a significant genetic influence is supported by multiple segregation analyses. Because genes associated with onset age may represent invaluable therapeutic targets to delay the disease, we sought to identify such genetic modifiers using a genomewide association study in familial PD. There have been previous genomewide association studies (GWAS) to identify genes influencing PD susceptibility, but this is the first to identify genes contributing to the variation in onset age. Methods: Initial analyses were performed using genotypes generated with the Illumina HumanCNV370Duo array in a sample of 857 unrelated, familial PD cases. Subsequently, a meta-analysis of imputed SNPs was performed combining the familial PD data with that from a previous GWAS of 440 idiopathic PD cases. The SNPs from the meta-analysis with the lowest p-values and consistency in the direction of effect for onset age were then genotyped in a replication sample of 747 idiopathic PD cases from the Parkinson Institute Biobank of Milan, Italy. Results: Meta-analysis across the three studies detected consistent association (p < 1 × 10-5) with five SNPs, none of which reached genomewide significance. On chromosome 11, the SNP with the lowest p-value (rs10767971; p = 5.4 × 10-7) lies between the genes QSER1 and PRRG4. Near the PARK3 linkage region on chromosome 2p13, association was observed with a SNP (rs7577851; p = 8.7 × 10-6) which lies in an intron of the AAK1 gene. This gene is closely related to GAK, identified as a possible PD susceptibility gene in the GWAS of the familial PD cases. Conclusion: Taken together, these results suggest an influence of genes involved in endocytosis and lysosomal sorting in PD pathogenesis.

Original languageEnglish
Article number1471
Pages (from-to)98
Number of pages1
JournalBMC Medical Genetics
Volume10
DOIs
StatePublished - Sep 22 2009

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Age of Onset
Parkinson Disease
Single Nucleotide Polymorphism
Genes
Meta-Analysis
Disease Susceptibility
Heritable Quantitative Trait
Chromosomes, Human, Pair 11
Endocytosis
Introns
Italy
Chromosomes
Genotype

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Latourelle, J. C., Pankratz, N., Dumitriu, A., Wilk, J. B., Goldwurm, S., Pezzoli, G., ... Foroud, T. (2009). Genomewide association study for onset age in Parkinson disease. BMC Medical Genetics, 10, 98. [1471]. https://doi.org/10.1186/1471-2350-10-98

Genomewide association study for onset age in Parkinson disease. / Latourelle, Jeanne C.; Pankratz, Nathan; Dumitriu, Alexandra; Wilk, Jemma B.; Goldwurm, Stefano; Pezzoli, Gianni; Mariani, Claudio B.; DeStefano, Anita L.; Halter, Cheryl; Gusella, James F.; Nichols, William C.; Myers, Richard H.; Foroud, Tatiana.

In: BMC Medical Genetics, Vol. 10, 1471, 22.09.2009, p. 98.

Research output: Contribution to journalArticle

Latourelle, JC, Pankratz, N, Dumitriu, A, Wilk, JB, Goldwurm, S, Pezzoli, G, Mariani, CB, DeStefano, AL, Halter, C, Gusella, JF, Nichols, WC, Myers, RH & Foroud, T 2009, 'Genomewide association study for onset age in Parkinson disease', BMC Medical Genetics, vol. 10, 1471, pp. 98. https://doi.org/10.1186/1471-2350-10-98
Latourelle JC, Pankratz N, Dumitriu A, Wilk JB, Goldwurm S, Pezzoli G et al. Genomewide association study for onset age in Parkinson disease. BMC Medical Genetics. 2009 Sep 22;10:98. 1471. https://doi.org/10.1186/1471-2350-10-98
Latourelle, Jeanne C. ; Pankratz, Nathan ; Dumitriu, Alexandra ; Wilk, Jemma B. ; Goldwurm, Stefano ; Pezzoli, Gianni ; Mariani, Claudio B. ; DeStefano, Anita L. ; Halter, Cheryl ; Gusella, James F. ; Nichols, William C. ; Myers, Richard H. ; Foroud, Tatiana. / Genomewide association study for onset age in Parkinson disease. In: BMC Medical Genetics. 2009 ; Vol. 10. pp. 98.
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abstract = "Background: Age at onset in Parkinson disease (PD) is a highly heritable quantitative trait for which a significant genetic influence is supported by multiple segregation analyses. Because genes associated with onset age may represent invaluable therapeutic targets to delay the disease, we sought to identify such genetic modifiers using a genomewide association study in familial PD. There have been previous genomewide association studies (GWAS) to identify genes influencing PD susceptibility, but this is the first to identify genes contributing to the variation in onset age. Methods: Initial analyses were performed using genotypes generated with the Illumina HumanCNV370Duo array in a sample of 857 unrelated, familial PD cases. Subsequently, a meta-analysis of imputed SNPs was performed combining the familial PD data with that from a previous GWAS of 440 idiopathic PD cases. The SNPs from the meta-analysis with the lowest p-values and consistency in the direction of effect for onset age were then genotyped in a replication sample of 747 idiopathic PD cases from the Parkinson Institute Biobank of Milan, Italy. Results: Meta-analysis across the three studies detected consistent association (p < 1 × 10-5) with five SNPs, none of which reached genomewide significance. On chromosome 11, the SNP with the lowest p-value (rs10767971; p = 5.4 × 10-7) lies between the genes QSER1 and PRRG4. Near the PARK3 linkage region on chromosome 2p13, association was observed with a SNP (rs7577851; p = 8.7 × 10-6) which lies in an intron of the AAK1 gene. This gene is closely related to GAK, identified as a possible PD susceptibility gene in the GWAS of the familial PD cases. Conclusion: Taken together, these results suggest an influence of genes involved in endocytosis and lysosomal sorting in PD pathogenesis.",
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