High-depth whole-genome sequencing identifies structure variants, copy number variants and short tandem repeats associated with Parkinson’s disease

Abstract While numerous single nucleotide variants and small indels have been identified in Parkinson’s disease (PD), the genome-wide contribution of structural variants (SVs), copy number variants (CNVs) and short tandem repeats (STRs) remains poorly understood. Here we investigated the association between these variants and PD using the high-depth whole-genome sequencing data from 466 PD patients and 513 healthy elderlies. A total of 29,561 SVs, 32,153 CNVs and 174,905 STRs were detected. Overall, CNV deletions were significantly enriched in the end-proportion of autosomal chromosomes in PD. Genome-wide association study identified 11 novel signals (1 SV, 4 CNVs and 6 STRs) reaching genome-wide significance. Among these, the deletion nearby MUC19 and the 5-copy GGGAAA repeat in SLC2A13 reduced the penetrance of LRRK2 G2385R variant. Moreover, genes with these variants were specifically expressed in dopaminergic neurons and highly dosage-sensitive. These data provided novel insights into the genetic architecture of PD.