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

Abstract

Background: PD is a complex polygenic disorder. In recent years, several genes from the endocytic membrane-trafficking pathway have been suggested to contribute to disease etiology. However, a systematic analysis of pathway-specific genetic risk factors is yet to be performed.

Objectives: To comprehensively study the role of the endocytic membrane-trafficking pathway in the risk of PD.

Methods: Linkage disequilibrium score regression was used to estimate PD heritability explained by 252 genes involved in the endocytic membrane-trafficking pathway including genome-wide association studies data from 18,869 cases and 22,452 controls. We used pathway-specific single-nucleotide polymorphisms to construct a polygenic risk score reflecting the cumulative risk of common variants. To prioritize genes for follow-up functional studies, summary-data based Mendelian randomization analyses were applied to explore possible functional genomic associations with expression or methylation quantitative trait loci.

Results: The heritability estimate attributed to endocytic membrane-trafficking pathway was 3.58% (standard error = 1.17). Excluding previously nominated PD endocytic membrane-trafficking pathway genes, the missing heritability was 2.21% (standard error = 0.42). Random heritability simulations were estimated to be 1.44% (standard deviation = 0.54), indicating that the unbiased total heritability explained by the endocytic membrane-trafficking pathway was 2.14%. Polygenic risk score based on endocytic membrane-trafficking pathway showed a 1.25 times increase of PD risk per standard deviation of genetic risk. Finally, Mendelian randomization identified 11 endocytic membrane-trafficking pathway genes showing functional consequence associated to PD risk.

Conclusions: We provide compelling genetic evidence that the endocytic membrane-trafficking pathway plays a relevant role in disease etiology. Further research on this pathway is warranted given that critical effort should be made to identify potential avenues within this biological process suitable for therapeutic interventions. © 2019 International Parkinson and Movement Disorder Society.

Keywords: Parkinson's disease; endocytosis; genetic risk; heritability; polygenic risk score.

Figure 1.. Biological implication of EMPT genes in DA neurons.

A. Top 10 significant Enriched Reactome Pathways with an adjusted False Discovery Rate p-value < 0.05. Pathway enrichment analysis was performed using Panther. Only the TOP 10 enriched pathways were selected for visualization. B. Overlap between genes expressed in DA neurons and EMTP gene set. The EMTP human gene were transform in their mouse homolog genes. From the 252 total human genes, a total of 244 were found in mouse (Table S3). The DA neuron gene expression were obtain from GSE76381) (La Manno et al. 2016) after an arbitrary selected threshold of expression.

Figure 2.. Polygenic Risk Score across EMTP.

Forest plots of PRS estimates across cohorts. For each effect estimate, the size of the square is proportional to the size of the study, with 95% confidence intervals as horizontal error bars. The random-effects estimates are represented by the red diamond, with fixed-effects in blue, and the centerline of each diamond representing the summary PRS estimate. The number of samples per cohort are reported as follows: SHULMAN: 789 cases and 195 controls, MCGILL: 583 cases and 906 controls, SPAIN3: 2120 cases and 1333 controls, TUBI: 741 cases and 944 controls, VANCE: 621 cases and 303 controls, OSLO: 476 cases and 462 controls, HBS:, PDBP: 543 cases and 284 controls, FINLAND: 386 cases and 493 controls, PPMI: 363 cases and 165 controls.