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Multicenter Study

Dissection of the genetics of Parkinson's disease identifies an additional association 5' of SNCA and multiple associated haplotypes at 17q21

UK Parkinson's Disease Consortium et al. Hum Mol Genet. .

Abstract

We performed a genome-wide association study (GWAS) in 1705 Parkinson's disease (PD) UK patients and 5175 UK controls, the largest sample size so far for a PD GWAS. Replication was attempted in an additional cohort of 1039 French PD cases and 1984 controls for the 27 regions showing the strongest evidence of association (P< 10(-4)). We replicated published associations in the 4q22/SNCA and 17q21/MAPT chromosome regions (P< 10(-10)) and found evidence for an additional independent association in 4q22/SNCA. A detailed analysis of the haplotype structure at 17q21 showed that there are three separate risk groups within this region. We found weak but consistent evidence of association for common variants located in three previously published associated regions (4p15/BST1, 4p16/GAK and 1q32/PARK16). We found no support for the previously reported SNP association in 12q12/LRRK2. We also found an association of the two SNPs in 4q22/SNCA with the age of onset of the disease.

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Figures

Figure 1.
Figure 1.
Genome-wide association plot. Genome-wide association results for PD at 532, 616 SNPs. Alternating chromosomes are show in shades of blue. Previously identified loci that also replicate in this study are highlighted in green.
Figure 2.
Figure 2.
Haplotype tagging of three risk groups identified at the 17q21 locus. The tree shown represents the estimated ancestral relationship between HapMap 2 chromosomes at position 41.19 Mb on chromosome 17 (note that the tree is not scaled relative to time). GENECLUSTER analysis identified three risk groups defined by the braches subtending the blue, green and red circles which represent putative mutation events. Shown on the left are haplotypes delineated by four SNPs chosen to tag the three risk groups. Each chromosome carrying the allele listed by the rsID at the top the figure is coloured according to the haplotype group to which they are assigned. The green haplotypes demark the two orientations labelled H1 and H2, of the large inversion polymorphism encompassing the 17q21 region (see text).
See this image and copyright information in PMC

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