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


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.

SUBMITTER: Butcher NJ 

PROVIDER: S-EPMC5400231 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Publications

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

Butcher Nancy J NJ   Merico Daniele D   Zarrei Mehdi M   Ogura Lucas L   Marshall Christian R CR   Chow Eva W C EWC   Lang Anthony E AE   Scherer Stephen W SW   Bassett Anne S AS  

PloS one 20170421 4


<h4>Objectives</h4>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.<h4>Methods</h4>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 c  ...[more]

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