Missing heritability in Parkinson's disease: the emerging role of non-coding genetic variation

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder caused by a complex interplay of genetic and environmental factors. For the stratification of PD patients and the development of advanced clinical trials, including causative treatments, a better understanding of the underlying genetic architecture of PD is required. Despite substantial efforts, genome-wide association studies have not been able to explain most of the observed heritability. The majority of PD-associated genetic variants are located in non-coding regions of the genome. A systematic assessment of their functional role is hampered by our incomplete understanding of genotype-phenotype correlations, for example through differential regulation of gene expression. Here, the recent progress and remaining challenges for the elucidation of the role of non-coding genetic variants is reviewed with a focus on PD as a complex disease with multifactorial origins. The function of gene regulatory elements and the impact of non-coding variants on them, and the means to map these elements on a genome-wide level, will be delineated. Moreover, examples of how the integration of functional genomic annotations can serve to identify disease-associated pathways and to prioritize disease- and cell type-specific regulatory variants will be given. Finally, strategies for functional validation and considerations for suitable model systems are outlined. Together this emphasizes the contribution of rare and common genetic variants to the complex pathogenesis of PD and points to remaining challenges for the dissection of genetic complexity that may allow for better stratification, improved diagnostics and more targeted treatments for PD in the future.

Keywords: Gene regulation; Genetic modifier; Genetic susceptibility; Genome-wide association studies; Non-coding variation; Parkinson’s disease; Polygenic risk scores.

Fig. 1

Overview of non-coding variants in ClinVar (27 Nov 2019). Results show the remaining variants after filtering for non-coding regions (‘Splice-D/A’, ‘3-UTR’, ‘5-UTR’, ‘Non-coding’, ‘intronic’), considering only curated variants defined by their reviewer status (‘Criteria provided/multiple submitters, no conflicts’, ‘Criteria provided, single submitter’, ‘Reviewed by expert panel’). Figure adapted from Simple ClinVar results

Fig. 2

Examples for cis and trans acting genetic variants. Cis acting variants can affect proximal or distal elements resulting in changes in gene expression. Effects in trans alter the abundance or nature of an intermediate factor resulting in altered expression of the target gene. This can be through both coding and non-coding variants

Fig. 3

Overview of DNA- and histone-modifications, chromatin conformation and 3D organization of the chromosome. a Schematic presentation of DNA- and chromatin marks and chromatin accessibility. b Chromatin organization into separated domains, Cohesins and CTCF transcription factors establish domain boundaries. Enhancer and promoter elements can interact within TADs but not with neighboring elements in adjacent TADs. Enhancers are marked yellow, promoters green and gene bodies brown. c Idealized next generation sequencing tracks on chromosome conformation capture sequencing using CTCF as bait map TADs, ChIP-seq identifies active enhancer histone marks, and ATAC-seq maps chromatin accessibility. Red arrows indicate how they can be translated into functional annotations mapped to the genome

Fig. 4

Exemplary prioritization approach for non-coding GWAS variants located in cell type specific gene regulatory element. Cell type resolved information on enhancer marks and chromatin accessibility reduces the number of potential candidate variants. TF footprinting allows to prioritize variants that disrupt TF binding motifs, target genes are identified through chromosome conformation capture techniques. Here an exemplary non-coding variant is identified in an enhancer element that interacts with the promoter of gene 1 in a DA neuron specific manner