Abstract
ObjectivesTo 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.MethodsIn 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.ResultsNo 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.ConclusionsThe 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.
Highlights
Over the past two decades new knowledge has elucidated a genetic basis for an increasing proportion of patients with Parkinson’s disease (PD) [1]
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 generation sequencing for studying the etiology of PD
Summary
Over the past two decades new knowledge has elucidated a genetic basis for an increasing proportion of patients with Parkinson’s disease (PD) [1]. We identified the hemizygous 22q11.2 microdeletion associated with 22q11.2 deletion syndrome (22q11.2DS; OMIM #192430, #188400) as a novel genetic risk factor for neuropathologically confirmed, L-dopa responsive early-onset PD [2]. To maximize statistical power in this initial study, we investigated rare variant burden for gene-sets with higher a priori likelihood of contributing to PD risk. These included variants affecting candidate genes in the 22q11.2 deletion region, such as COMT, SEPT5, and six mitochondrial function genes, as well as other genome-wide PD-relevant gene-sets. We found evidence for rare variants outside the 22q11.2 region perturbing gene networks relevant to PD, supporting the utility of this genetic model for early-onset PD
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