Open AccessWhole-genome sequencing suggests mechanisms for 22q11.2 deletion-associated Parkinson’s disease
Author(s) -
Nancy J. Butcher,
Daniele Merico,
Mehdi Zarrei,
Lucas Ogura,
Christian R. Marshall,
Eva W.C. Chow,
Anthony E. Lang,
Stephen W. Scherer,
Anne S. Bassett
Publication year - 2017
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0173944
Subject(s) - genetics , locus (genetics) , missense mutation , candidate gene , biology , gene , disease , genome wide association study , whole genome sequencing , mutation , genotype , genome , single nucleotide polymorphism , medicine
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.