Expanding Parkinson’s disease genetics: novel risk loci, genomic context, causal insights and heritable risk

Abstract

We performed the largest genome-wide association study of PD to date, involving the analysis of 7.8M SNPs in 37.7K cases, 18.6K UK Biobank proxy-cases, and 1.4M controls. We identified 90 independent genome-wide significant signals across 78 loci, including 38 independent risk signals in 37 novel loci. These variants explained 26-36% of the heritable risk of PD. Tests of causality within a Mendelian randomization framework identified putatively causal genes for 70 risk signals. Tissue expression enrichment analysis suggested that signatures of PD loci were heavily brain-enriched, consistent with specific neuronal cell types being implicated from single cell expression data. We found significant genetic correlations with brain volumes, smoking status, and educational attainment. In sum, these data provide the most comprehensive understanding of the genetic architecture of PD to date by revealing many additional PD risk loci, providing a biological context for these risk factors, and demonstrating that a considerable genetic component of this disease remains unidentified.

The endocytic membrane trafficking pathway plays a major role in the risk of Parkinson's disease

“…Clinical and demographic characteristics of the cohorts under study are shown in Supporting Information Table S1. Additional details of these cohorts can be found in Nalls and colleagues …”

“…Quality‐control (QC) procedures in the IPDGC GWAS data set have been previously described elsewhere . In brief, samples with call rates <95% and whose genetically determined sex from X chromosome heterogeneity did not match that from clinical data were excluded.…”

“…For the risk‐profiling analysis, we mirrored the workflow used in the most recent PD meta‐analysis to date, with the exception that before running this analysis pipeline, we extracted only genotypes from the pathway of interest. In brief, PRS profiling is calculated traditionally based on weighted allele dose manner as per previous work .…”

“…We utilized two‐sample Mendelian randomization to investigate possible functional genomic associations between nominated variants of interest in the EMTP pathway versus expression and methylation patterns. Quantitative trait loci (QTL) association summary statistics across well‐curated methylation and expression data sets from the SMR (http://cnsgenomics.com/software/smr) were compared to PD outcome summary statistics after extracting the pathway‐specific variants considered as the instrumental variables. These include estimates for methylation and cis‐expression from the Genotype‐Tissue Expression (GTEx) Consortium (v6; whole blood and 10 brain regions), the CommonMind Consortium (CMC; dorsolateral prefrontal cortex), the Religious Orders Study and Memory and Aging Project (ROSMAP), and the Brain eQTL Almanac project (Braineac; 10 brain regions), as reported elsewhere.…”

“…As expected from complex diseases, the PD‐related signals identified to date only account for a small proportion of the total phenotypic variation, defined as heritability . It is estimated that only around 10% to 15% of the overall heritable risk of PD is explained by current genome‐wide association studies (GWAS) . The most plausible explanation for the “missing heritability” might be small effect sizes of the yet to be discovered risk loci which do not reach GWAS significance, as well as structural genomic and rare variation poorly covered by current technology .…”