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PLoS One. 2017 Apr 21;12(4):e0173944. doi: 10.1371/journal.pone.0173944. eCollection 2017.

Whole-genome sequencing suggests mechanisms for 22q11.2 deletion-associated Parkinson's disease.

Butcher NJ1,2,3, Merico D4, Zarrei M4, Ogura L1, Marshall CR4,5, Chow EWC1,2,6, Lang AE3,7,8,9,10, Scherer SW3,4,5, Bassett AS1,2,3,6,11,12,13,14.

Author information

1
Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
2
Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
3
Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
4
The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
5
McLaughlin Centre and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
6
Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
7
Division of Neurology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
8
Tanz Centre for Research in Neurodegenerative Diseases, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
9
Toronto Western Hospital Research Institute, University Health Network, Toronto, Ontario, Canada.
10
Edmond J. Safra Program in Parkinson's Disease, Toronto Western Hospital, Toronto, Ontario, Canada.
11
Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
12
The Dalglish 22q Clinic for Adults with 22q11.2 Deletion Syndrome, University Health Network, Toronto, Ontario, Canada.
13
Department of Psychiatry, University Health Network, Toronto, Ontario, Canada.
14
Division of Cardiology, Department of Medicine, University Health Network, Toronto, Ontario, Canada.

Abstract

OBJECTIVES:

To investigate disease risk mechanisms of early-onset Parkinson's disease (PD) associated with the recurrent 22q11.2 deletion, a genetic risk factor for early-onset PD.

METHODS:

In a proof-of-principle study, we used whole-genome sequencing (WGS) to investigate sequence variants in nine adults with 22q11.2DS, three with neuropathologically confirmed early-onset PD and six without PD. Adopting an approach used recently to study schizophrenia in 22q11.2DS, here we tested candidate gene-sets relevant to PD.

RESULTS:

No mutations common to the cases with PD were found in the intact 22q11.2 region. While all were negative for rare mutations in a gene-set comprising PD disease-causing and risk genes, another candidate gene-set of 1000 genes functionally relevant to PD presented a nominally significant (P = 0.03) enrichment of rare putatively damaging missense variants in the PD cases. Polygenic score results, based on common variants associated with PD risk, were non-significantly greater in those with PD.

CONCLUSIONS:

The results of this first-ever pilot study of WGS in PD suggest that the cumulative burden of genome-wide sequence variants may contribute to expression of early-onset PD in the presence of threshold-lowering dosage effects of a 22q11.2 deletion. We found no evidence that expression of PD in 22q11.2DS is mediated by a recessive locus on the intact 22q11.2 chromosome or mutations in known PD genes. These findings offer initial evidence of the potential effects of multiple within-individual rare variants on the expression of PD and the utility of next generation sequencing for studying the etiology of PD.

PMID:
28430790
PMCID:
PMC5400231
DOI:
10.1371/journal.pone.0173944
[Indexed for MEDLINE]
Free PMC Article

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