Genomewide association study for onset age in Parkinson disease

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 x 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 x 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 x 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.

Figure 1

Forest plots showing study-specific and pooled effects for top six results in final meta-analysis. The effect (in years) on age at PD onset and 95% confidence intervals for the indicated genetic model are shown for each of the three independent samples and the combined analysis. A. Additive model of the A allele in SNP rs17565841 B. Dominant model of the A allele in SNP rs17565841 C. Dominant model of the C allele in SNP rs1941184 D. Dominant model of the A allele in SNP rs10918270 E. Recessive model of the T allele in SNP rs10767971 F. Recessive model of the T allele in SNP rs7577851.

Figure 2

Evidence of association in Chromosome 11 region. Along the x axis is the physical position in the region (in kB) with known genes shown in their orientation The left Y-axis denotes the association test result as -log(p-value) corresponding to diamonds in the figure. The blue diamond identifies the primary SNP result labeled with an rs# and p-value. The color of additional diamonds depicts the pairwise linkage disequilibrium with the primary SNP: red indicates r² > 0.8, orange 0.5 < r² < 0.8, yellow 0.2 < r² < 0.5, white r² < 0.2, grey unknown LD. R² values were obtained from the CEPH HapMap data. The right Y-axis indicates the recombination rate, also obtained from CEPH HapMap data, and shown within the figure by the solid light-blue line. A. Recessive model B. Dominant model.