The genetic architecture of Parkinson's disease

Blauwendraat, Cornelis; Nalls, Mike A.; Singleton, Andrew B.

doi:10.1016/s1474-4422(19)30287-x

Cited by 801 publications

(732 citation statements)

References 66 publications

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“…Although a great deal of progress in understanding the genetic underpinnings of familial and sporadic Parkinson disease (PD) has been made, the biological basis and cellular context of this risk remains unclear. We have learned that about 1-2 % of PD is associated with a classical Mendelian inheritance pattern, while the majority of disease is driven by a complex set of factors in which polygenic risk seems to play a crucial role [4]. The fact that many of the genes that contain disease-causing mutations also map within risk loci identified by genome-wide association studies (GWAS), supports the notion that common pathways are involved in both forms, and therefore these pleomorphic genes might interact to regulate downstream common targets in both monogenic and non-monogenic PD [22].…”

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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“…Among these, mutations in the SNCA gene were the first to be identified. More recently, genome wide association studies have identified additional genetic variants in PD (Blauwendraat, Nalls, & Singleton, ), DLB (Orme, Guerreiro, & Bras, ), and MSA (Katzeff, Phan, Purushothuman, Halliday, & Kim, ). These findings suggest a complex interplay between genetics, aging, and environmental factors in the various synucleinopathies.…”

Section: Genes Phenotypes and Terminologymentioning

confidence: 99%

Synucleinopathies: Where we are and where we need to go

Brás

Dominguez-Meijide

Gerhardt

et al. 2020

Journal of Neurochemistry

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All authors contributed equally to this manuscript. This artic le is relat ed to the Speci al Issue "Synuc lein" Abbreviations: A30P, aSyn substitution of an alanine for a proline at position 30; A53E, aSyn substitution of an alanine for a glutamic acid at position 53; A53T, aSyn substitution of an alanine for a tyrosine at position 53; ALP, autophagy-lysosomal pathway; APLP1, Aβ precursor-like protein 1; aSyn, alpha-synuclein; BiFC, bimolecular fluorescence complementation; CMA, Chaperone-mediated autophagy; CNS, central nervous system; co-IP, co-immunoprecipitation; Cryo-EM, cryo-electron microscopy; CSF, cerebrospinal fluid; Cu, copper; DLB, dementia with Lewy bodies; E46K, aSyn substitution of a glutamic acid for a lysine at position 46; ENS, enteric nervous system; ER, endoplasmic reticulum; Fe, iron; FRET, fluorescence resonance energy transfer; G51D, aSyn substitution of a glycine for a aspartic acid at position 51Abstract Synucleinopathies are a group of disorders characterized by the accumulation of inclusions rich in the a-synuclein (aSyn) protein. This group of disorders includes Parkinson's disease, dementia with Lewy bodies (DLB), multiple systems atrophy, and pure autonomic failure (PAF). In addition, genetic alterations (point mutations and multiplications) in the gene encoding for aSyn (SNCA) are associated with familial forms of Parkinson's disease, the most common synucleinopathy. The Synuclein Meetings are a series that has been taking place every 2 years for about 12 years. The Synuclein Meetings bring together leading experts in the field of Synuclein and related human conditions with the goal of discussing and advancing the research. In 2019, the Synuclein meeting took place in Ofir, a city in the outskirts of Porto, Portugal. The meeting, entitled "Synuclein Meeting 2019:Where we are and where we need to go", brought together >300 scientists studying both clinical and molecular aspects of synucleinopathies. The meeting covered a many of the open questions in the field, in a format that prompted open discussions between the participants, and underscored the need for additional research that, hopefully, will lead to future therapies for a group of as of yet incurable disorders. Here, we provide a summary of the topics discussed in each session and highlight what we know, what we do not know, and what progress needs to be made in order to enable the field to continue to advance. We are confident this systematic assessment of where we stand will be useful to steer the field and contribute to filling knowledge gaps that may form the foundations for future therapeutic strategies, which is where we need to go.

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“…No significant gene ontology (GO) enrichment was observed, however, the top GO term detected was the Regulation of Microtubule Cytoskeleton Organization (GO:0070507) which was driven by nine URV containing genes: AKAP9, APC, CAMSAP2, CDK5RAP2, CEP120, CKAP2, CYLD, KIF11 and TPR (Supplementary Table 14). After including 25 known and suggested PD genes 17 ( Supplementary Table 15 FGF8, HYOU1, ITSN1, PPP5C, MAP3K5, NAE1, and SIRT1. We next repeated this analysis, but now including 303 genes tagged by the 90 PD GWAS loci 1 , which also yielded a significant network (STRING P <1x10 -16 , Supplementary Fig.…”

Section: Gene-wise Burden and Ppi Analysismentioning

confidence: 99%

Whole-exome analysis in Parkinson’s disease reveals a high burden of ultra rare variants in early onset cases

Bustos¹,

Krainc²,

Lubbe³

2020

Preprint

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Word count: Abstract = 208Main text = 4,362 (3,285 excluding Methods) ABSTRACTParkinson's disease (PD) is a complex neurodegenerative disorder with a strong genetic component. We performed a "hypothesis-free" exome-wide burden-based analysis of different variant frequencies, predicted functional impact and age of onset classes, in order to expand the understanding of rare variants in PD. Analyzing whole-exome data from a total of 1,425 PD cases and 596 controls, we found a significantly increased burden of ultra-rare (URV= private variants absent from gnomAD) protein altering variants (PAV) in early-onset PD cases (EOPD, <40 years old; P=3.95x10 -26 , beta=0.16, SE=0.02), compared to LOPD cases (>60 years old, late-onset), where more common PAVs (allele frequencies <0.001) showed the highest significance and effect (P=0.026, beta=0.15, SE=0.07). Gene-set burden analysis of URVs in EOPD highlighted significant disease-and tissue-relevant genes, pathways and protein-protein interaction networks that were different to that observed in non-EOPD cases. Heritability estimates revealed that URVs account for 15.9% of the genetic component in EOPD individuals. Our results suggest that URVs play a significant role in EOPD and that distinct etiological bases may exist for EOPD and sporadic PD. By providing new insights into the genetic architecture of PD, our study may inform approaches aimed at novel gene discovery and provide new directions for genetic risk assessment based on disease age of onset.

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The genetic architecture of Parkinson's disease

Cited by 801 publications

References 66 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

Synucleinopathies: Where we are and where we need to go

Whole-exome analysis in Parkinson’s disease reveals a high burden of ultra rare variants in early onset cases

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