Parkinson disease age of onset GWAS: defining heritability, genetic loci and a-synuclein mechanisms

摘要: Abstract Increasing evidence supports an extensive and complex genetic contribution to Parkinson’s disease (PD). Previous genome-wide association studies (GWAS) have shed light on the basis of risk for this disease. However, determinants PD age onset are largely unknown. Here we performed GWAS based 28,568 cases. We estimated that heritability due common variation was ~0.11, lower than overall (~0.27) likely in part because subjective nature measure. found two significant signals, one at SNCA other a protein-coding variant TMEM175, both which known loci Bonferroni corrected effect loci, INPP5F/BAG3, FAM47E/SCARB2, MCCC1. In addition, identified GBA coding carriers had earlier compared non-carriers. Notably, SNCA, SCARB2, BAG3 all been shown either directly influence alpha-synuclein aggregation or implicated pathways. Remarkably, well-established such as GCH1, MAPT RAB7L1/NUCKS1 (PARK16) did not show PD. While some may be measure power, is clearly case locus; thus variability locus influences whether but when individual develops believe important mechanistic therapeutic distinction. Furthermore, these data support model lysosomal mechanisms impact only also highlights therapies target more disease-modifying targeting