Mendelian genes for Parkinson's disease contribute to the sporadic forms of the disease†

Abstract

Parkinson's disease (PD) can be divided into familial (Mendelian) and sporadic forms. A number of causal genes have been discovered for the Mendelian form, which constitutes 10-20% of the total cases. Genome-wide association studies have successfully uncovered a number of susceptibility loci for sporadic cases but those only explain a small fraction (6-7%) of PD heritability. It has been observed that some genes that confer susceptibility to PD through common risk variants also contain rare causing mutations for the Mendelian forms of the disease. These results suggest a possible functional link between Mendelian and sporadic PD and led us to investigate the role that rare and low-frequency variants could have on the sporadic form. Through a targeting approach, we have resequenced at 49× coverage the exons and regulatory regions of 38 genes (including Mendelian and susceptibility PD genes) in 249 sporadic PD patients and 145 unrelated controls of European origin. Unlike susceptibility genes, Mendelian genes show a clear general enrichment of rare functional variants in PD cases, observed directly as well as with Tajima's D statistic and several collapsing methods. Our findings suggest that rare variation on PD Mendelian genes may have a role in the sporadic forms of the disease.

Detection of genomic rearrangements from targeted resequencing data in Parkinson's disease patients

“…Besides the detected structural variants, other functional alterations (including several known PD Mendelian mutations) had been previously detected in the same dataset 8. Frequencies and details are presented in Table 1 and Appendix 4 (Supplemental Data).…”

“…Our study of structural genetic alterations across the 38 PD‐associated genes previously sequenced through NGS8 disclosed a total of 11 structural variants in the PARK2 , GBA, and DJ1 genes, affecting 10 of 249 PD cases. All of these genomic alterations were predicted by the XHMM sofware3 (see details in Table S1) and were subsequently validated by quantitative PCR (Figure 1 and Figure S1).…”

“…Targeted resequencing data from 394 individuals including 249 idiopathic PD cases and 145 unrelated controls of European origin were compiled from Spataro et al (2015) 8. Details on eligibility criteria, clinical and demographic features of PD patients and targeting resequencing design are available in Appendix 1 (Supplementary Data).…”

“…The mean coverage per target and sample was 49.39X, and 91% of the target bases were covered at ≥15X depth 8. The detection of CNVs was performed with the XHMM software, which uses principal component analysis normalization and a hidden Markov model to detect and genotype CNVs from normalized read‐depth data from targeted sequencing experiments 3.…”

“…In particular, we used our own resequencing data of 38 PD‐associated genes in 249 PD cases and 145 unrelated controls of European ancestry8 to study the presence of structural variants predicted by eXome‐Hidden Markov Model (XHMM) software (https://atgu.mgh.harvard.edu/xhmm/), which was specifically developed to recover information on copy number variation from normalized read depth data obtained from targeted sequencing experiments 3. Subsequently, all the predicted CNVs were validated through quantitative polymerase chain reaction (PCR).…”