Genetics of Parkinson's disease: An introspection of its journey towards precision medicine

Bandrés‐Ciga, Sara; Díez-Fairén, Mónica; Kim, Jonggeol Jeff; Singleton, Andrew B.

doi:10.1016/j.nbd.2020.104782

Cited by 254 publications

(207 citation statements)

References 143 publications

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“…Several common molecular processes have been suggested as critical in PD pathophysiology, including lysosome mediated autophagy, mitochondrial dysfunction, endosomal protein sorting and recycling, immune response, and synaptic transmission [3]. A goal in much of this work has been to unify the proteins encoded by PD-linked genes into common pathways.…”

Section: Introductionmentioning

confidence: 99%

Large-scale pathway-specific polygenic risk, transcriptomic community networks and functional inferences in Parkinson disease

Bandrés‐Ciga

Sáez-Atiénzar

Kim

et al. 2020

Preprint

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Polygenic inheritance plays a central role in Parkinson disease (PD). A priority in elucidating PD etiology lies in defining the biological basis of genetic risk. Unraveling how risk leads to disruption will yield disease-modifying therapeutic targets that may be effective. Here, we utilized a high-throughput and hypothesis-free approach to determine biological pathways underlying PD using the largest currently available cohorts of genetic data and gene expression data from International Parkinson's Disease Genetics Consortium (IPDGC) andthe Accelerating Medicines Partnership -Parkinson's disease initiative (AMP-PD), among other sources. We placed these insights into a cellular context. We applied large-scale pathway-specific polygenic risk score (PRS) analyses to assess the role of common variation on PD risk in a cohort of 457,110 individuals by focusing on a compilation of 2,199 publicly annotated gene sets representative of curated pathways, of which we nominate 46 pathways associated with PD risk. We assessed the impact of rare variation on PD risk in an independent cohort of whole-genome sequencing data, including 4,331 individuals. We explored enrichment linked to expression cell specificity patterns using single-cell gene expression data and demonstrated a significant risk pattern for adult dopaminergic neurons, serotonergic neurons, and radial glia. Subsequently, we created a novel way of building de novo pathways by constructing a network expression community map using transcriptomic data derived from the blood of 1,612 PD patients, which revealed 54 connecting networks associated with PD. Our analyses highlight several promising pathways and genes for functional prioritization and provide a cellular context in which such work should be done.

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Section: Introductionmentioning

confidence: 99%

Large-scale pathway-specific polygenic risk, transcriptomic community networks and functional inferences in Parkinson disease

Bandrés‐Ciga

Sáez-Atiénzar

Kim

et al. 2020

Preprint

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“…up to~1.5-fold) but occur as commonly as 40% in the general population [5]. It is thought that the overall heritable component of disease is about 30% (5-10% due to monogenic causes and around 22% driven by common variants identified by genome-wide association studies) [6][7][8]. A prevailing hypothesis is that many of the identified genes and risk factors map into two closely related and overlapping cellular pathways: mitochondrial metabolism and autophagy.…”

Section: Genetic Underpinnings Of Parkinson's Diseasementioning

confidence: 99%

“…In addition, other pathways such as endosomal trafficking, synaptic transmission and immune response pathways have been identified to play a role in the pathogenesis of PD. [7,9] While these biological pathways have been linked to PD via genetic studies, it is very likely that dysfunction in these same pathways due to environmental exposures could also lead to PD. Figure 1 describes the genetic architecture of PD.…”

Section: Genetic Underpinnings Of Parkinson's Diseasementioning

confidence: 99%

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Emerging Targeted Therapeutics for Genetic Subtypes of Parkinsonism

2020

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In recent years, a precision medicine approach, which customizes medical treatments based on patients’ individual profiles and incorporates variability in genes, the environment, and lifestyle, has transformed medical care in numerous medical fields, most notably oncology. Applying a similar approach to Parkinson’s disease (PD) may promote the development of disease-modifying agents that could help slow progression or possibly even avert disease development in a subset of at-risk individuals. The urgent need for such trials partially stems from the negative results of clinical trials where interventions treat all PD patients as a single homogenous group. Here, we review the current obstacles towards the development of precision interventions in PD. We also review and discuss the clinical trials that target genetic forms of PD, i.e., GBA-associated and LRRK2-associated PD.

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“…Many factors likely constitute the “missing heritability”, including uncaptured genetic variation represented by (1) rare variants, (2) epigenetics and (3) structural variants (SV). As the contributions of both (1) and (2) have been explored in great detail in recent reviews [ 59 , 60 ], here we focus instead on the contribution of (3) SVs.…”

Section: The Limitations In Our Current Understanding Of Parkinsonmentioning

confidence: 99%

Genetic Risk Profiling in Parkinson’s Disease and Utilizing Genetics to Gain Insight into Disease-Related Biological Pathways

Hall

Bandrés‐Ciga

Díez-Fairén

et al. 2020

IJMS

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Parkinson’s disease (PD) is a complex disorder underpinned by both environmental and genetic factors. The latter only began to be understood around two decades ago, but since then great inroads have rapidly been made into deconvoluting the genetic component of PD. In particular, recent large-scale projects such as genome-wide association (GWA) studies have provided insight into the genetic risk factors associated with genetically ‘’complex’’ PD (PD that cannot readily be attributed to single deleterious mutations). Here, we discuss the plethora of genetic information provided by PD GWA studies and how this may be utilized to generate polygenic risk scores (PRS), which may be used in the prediction of risk and trajectory of PD. We also comment on how pathway-specific genetic profiling can be used to gain insight into PD-related biological pathways, and how this may be further utilized to nominate causal PD genes and potentially druggable therapeutic targets. Finally, we outline the current limits of our understanding of PD genetics and the potential contribution of variation currently uncaptured in genetic studies, focusing here on uncatalogued structural variants.

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Genetics of Parkinson's disease: An introspection of its journey towards precision medicine

Cited by 254 publications

References 143 publications

Large-scale pathway-specific polygenic risk, transcriptomic community networks and functional inferences in Parkinson disease

Large-scale pathway-specific polygenic risk, transcriptomic community networks and functional inferences in Parkinson disease

Emerging Targeted Therapeutics for Genetic Subtypes of Parkinsonism

Genetic Risk Profiling in Parkinson’s Disease and Utilizing Genetics to Gain Insight into Disease-Related Biological Pathways

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