Genetic identification of cell types underlying brain complex traits yields insights into the etiology of Parkinson’s disease

Bryois, Julien; Skene, Nathan G.; Hansen, Thomas Folkmann; Lja., Kogelman; Watson, Hunna J.; Liu, Z; Brueggeman, Leo; Breen, Gerome; Bulik, Cynthia M.; Arenas, Ernest; Hjerling-Leffler, Jens; Sullivan, Patrick F.

doi:10.1038/s41588-020-0610-9

Cited by 271 publications

(315 citation statements)

References 81 publications

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“…By integrating genetics and single-cell expression data, we found that PD risk is linked to expression specificity patterns in dopaminergic neurons, serotonergic neurons, and radial glia, suggesting that these cell types disrupt biological networks that impact PD risk. Although our study failed at replicating specific enrichment patterns for oligodendrocytes and microglia as previously reported using other approaches [18], our results are in concordance with previous literature that applies various methodologies to gain similar conclusions [5].…”

Section: Discussionsupporting

confidence: 93%

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: Discussionsupporting

confidence: 93%

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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“…In addition to human genetics, the canine behavioral GWAS's with and without control for body Our scRNA-seq findings are supported by studies that used human GWA genesets from diverse traits to identify relevant cells in scRNA-seq data 75 . For instance, educational attainment and schizophrenia showed a Spearman rank correlation of cell-type association of 0.94 because both were enriched for telencephalon projecting excitatory neurons out of the 39 cell types queried, and both associations were enriched for neurogenesis and synaptic processes genes.…”

Section: Discussionmentioning

confidence: 71%

Genome scans of dog behavior implicate a gene network underlying psychopathology in mammals, including humans

Zapata

Hecht

Serpell

et al. 2020

Preprint

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Genetic studies show a general factor associated with all human personality and psychopathology, but its basis is unknown. We performed genome scans of 17 normal and problem behaviors in three multi-breed dog cohorts. 21 of 90 mapped loci were supported for the same, or a related, trait in a second cohort. Several of those loci were also associated with brain structure differences across breeds; and five of the respective top-candidate genes are also associated with human brain structure and function. More broadly, the geneset of canine behavioral scans is supported by enrichment for genes mapped for human behavior, personality, psychopathology and brain structure. The biology implicated includes, neurogenesis, axon guidance, angiogenesis, brain structure, alternative splicing, disease association, Hox-family transcription factors, and subiculum expression. Because dog behavior is correlated with body size, we isolated the effect of body size/height in the dog mapping and in the comparative human UK Biobank analyses. Our dog and human findings are consistent with pleiotropy of diverse brain traits with energy metabolism, height, longevity and reproduction. We propose a genetic network underlies neuron birth and development across the life course, and is associated with evolutionary adaptation of behavior and the general psychopathology factor. This understanding has implications for all common psychiatric disorders, and suggests how their risk could be impacted by environmental effects on the IGF1/growth factor signaling-PI3K-AKT-mTOR axis.

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“…Recent single-nuclei transcriptomics in the substantia nigra support association of PD with dopaminergic neuron-specific gene expression and, interestingly, implicate oligodendrocyte-specific expression [ 39 ]. Similar single-cell transcriptomics in the mouse nervous system also confirm the association between dopaminergic neurons and PD, and reiterate the novel association with oligodendrocytes [ 40 ]. Additionally, the pathway analysis study mentioned previously integrated single-cell expression data to link PD risk to expression patterns in dopaminergic neurons, serotonergic neurons, hypothalamic GABAergic neurons and neural progenitors [ 38 ].…”

Section: Utilizing Genetic Risk Profiling To Identify Biological Pmentioning

confidence: 69%

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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Genetic identification of cell types underlying brain complex traits yields insights into the etiology of Parkinson’s disease

Abstract: Genetic identification of cell types underlying brain complex traits yields insights into the

Cited by 271 publications

References 81 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

Genome scans of dog behavior implicate a gene network underlying psychopathology in mammals, including humans

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

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