Fine-mapping of Parkinson’s disease susceptibility loci identifies putative causal variants

Abstract

Recent genome-wide association studies have identified 78 loci associated with Parkinson’s Disease susceptibility but the underlying mechanisms remain largely unclear. To identify variants likely causal for disease risk, we fine-mapped these Parkinson’s-associated loci using four different fine-mapping methods. We then integrated multi-assay cell-type-specific epigenomic profiles to pinpoint the likely mechanism of action of each variant, allowing us to identify Consensus SNPs that disrupt LRRK2 and FCGR2A regulatory elements in microglia, an MBNL2 enhancer in oligodendrocytes, and a DYRK1A enhancer in neurons. This genome-wide functional fine-mapping investigation of Parkinson’s Disease substantially advances our understanding of the causal mechanisms underlying this complex disease while avoiding focus on spurious, non-causal mechanisms. Together, these results provide a robust, comprehensive list of the likely causal variants, genes and cell-types underlying Parkinson’s Disease risk as demonstrated by consistently greater enrichment of our fine-mapped SNPs relative to lead GWAS SNPs across independent functional impact annotations. In addition, our approach prioritized an average of 3/85 variants per locus as putatively causal, making downstream experimental studies both more tractable and more likely to yield disease-relevant, actionable results.