PARK10 is a major locus for sporadic neuropathologically confirmed Parkinson disease
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Abstract
Objective: To minimize pathologic heterogeneity in genetic studies of Parkinson disease (PD), the Autopsy-Confirmed Parkinson Disease Genetics Consortium conducted a genome-wide association study using both patients with neuropathologically confirmed PD and controls.
Methods: Four hundred eighty-four cases and 1,145 controls met neuropathologic diagnostic criteria, were genotyped, and then imputed to 3,922,209 variants for genome-wide association study analysis.
Results: A small region on chromosome 1 was strongly associated with PD (rs10788972; p = 6.2 × 10−8). The association peak lies within and very close to the maximum linkage peaks of 2 prior positive linkage studies defining the PARK10 locus. We demonstrate that rs10788972 is in strong linkage disequilibrium with rs914722, the single nucleotide polymorphism defining the PARK10 haplotype previously shown to be significantly associated with age at onset in PD. The region containing the PARK10 locus was significantly reduced from 10.6 megabases to 100 kilobases and contains 4 known genes: TCEANC2, TMEM59, miR-4781, and LDLRAD1.
Conclusions: We confirm the association of a PARK10 haplotype with the risk of developing idiopathic PD. Furthermore, we significantly reduce the size of the PARK10 region. None of the candidate genes in the new PARK10 region have been previously implicated in the biology of PD, suggesting new areas of potential research. This study strongly suggests that reducing pathologic heterogeneity may enhance the application of genetic association studies to PD.
GLOSSARY
- ADGC=
- Alzheimer Disease Genetics Consortium;
- APDGC=
- Autopsy-Confirmed Parkinson Disease Genetics Consortium;
- CIDR=
- Center for Inherited Disease Research;
- GWAS=
- genome-wide association study;
- LD=
- linkage disequilibrium;
- MAF=
- minor allele frequency;
- OR=
- odds ratio;
- PCA=
- principal component analysis;
- PC1=
- principal component 1;
- PD=
- Parkinson disease;
- QC=
- quality control;
- SNP=
- single nucleotide polymorphism
Footnotes
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
Editorial, page 966
Supplemental data at Neurology.org
- Received April 22, 2014.
- Accepted in final form October 9, 2014.
- © 2015 American Academy of Neurology
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