Moving beyond neurons: the role of cell type-specific gene regulation in Parkinson’s disease heritability

Reynolds, Regina H.; Botía, Juan A.; Nalls, Mike A.; Gagliano, Sarah A.; Ryten, Mina

doi:10.1101/442152

Cited by 40 publications

(51 citation statements)

References 73 publications

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“…We observed for the first time in human a significant association between PD genetic risk and genes with DaN-specific expression patterns (q MAGMA = 4.6 × 10 −3 , Fig. 2a), supported by recent observations made using mouse expression patterns of predicted PD GWA-risk genes 13,14 and contrasting studies proposing that PD risk is not associated with neurons 15 . We also identified a second association between PD genetic risk and genes with ODC-specific expression patterns (q MAGMA = 0.035; Fig.…”

Section: Resultssupporting

confidence: 88%

A single-cell atlas of the human substantia nigra reveals cell-specific pathways associated with neurological disorders

et al. 2020

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We describe a human single-nuclei transcriptomic atlas for the substantia nigra (SN), generated by sequencing approximately 17,000 nuclei from matched cortical and SN samples. We show that the common genetic risk for Parkinson's disease (PD) is associated with dopaminergic neuron (DaN)-specific gene expression, including mitochondrial functioning, protein folding and ubiquitination pathways. We identify a distinct cell type association between PD risk and oligodendrocyte-specific gene expression. Unlike Alzheimer's disease (AD), we find no association between PD risk and microglia or astrocytes, suggesting that neuroinflammation plays a less causal role in PD than AD. Beyond PD, we find associations between SN DaNs and GABAergic neuron gene expression and multiple neuropsychiatric disorders. Conditional analysis reveals that distinct neuropsychiatric disorders associate with distinct sets of neuron-specific genes but converge onto shared loci within oligodendrocytes and oligodendrocyte precursors. This atlas guides our aetiological understanding by associating SN cell type expression profiles with specific disease risk.

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Section: Resultssupporting

confidence: 88%

A single-cell atlas of the human substantia nigra reveals cell-specific pathways associated with neurological disorders

et al. 2020

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“…Co-expression modules from UKBEC and GTEx were downloaded using the CoExpNets package (see 'URLs' section). As previously performed, modules were filtered to include only genes with module membership 5 0.5 (Reynolds et al, 2019). Furthermore, gene coordinates were extended by 100 kb upstream and downstream of their transcription start and end site, in order to capture regulatory elements that might contribute to disease heritability (Finucane et al, 2018).…”

Section: Stratified Linkage Disequilibrium Score Regressionmentioning

confidence: 99%

Dystonia genes functionally converge in specific neurons and share neurobiology with psychiatric disorders

Mencacci

Reynolds

García-Ruiz

et al. 2020

Brain

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Dystonia is a neurological disorder characterized by sustained or intermittent muscle contractions causing abnormal movements and postures, often occurring in absence of any structural brain abnormality. Psychiatric comorbidities, including anxiety, depression, obsessive-compulsive disorder and schizophrenia, are frequent in patients with dystonia. While mutations in a fast-growing number of genes have been linked to Mendelian forms of dystonia, the cellular, anatomical, and molecular basis remains unknown for most genetic forms of dystonia, as does its genetic and biological relationship to neuropsychiatric disorders. Here we applied an unbiased systems-biology approach to explore the cellular specificity of all currently known dystonia-associated genes, predict their functional relationships, and test whether dystonia and neuropsychiatric disorders share a genetic relationship. To determine the cellular specificity of dystonia-associated genes in the brain, single-nuclear transcriptomic data derived from mouse brain was used together with expression-weighted cell-type enrichment. To identify functional relationships among dystonia-associated genes, we determined the enrichment of these genes in co-expression networks constructed from 10 human brain regions. Stratified linkage-disequilibrium score regression was used to test whether co-expression modules enriched for dystonia-associated genes significantly contribute to the heritability of anxiety, major depressive disorder, obsessive-compulsive disorder, schizophrenia, and Parkinson’s disease. Dystonia-associated genes were significantly enriched in adult nigral dopaminergic neurons and striatal medium spiny neurons. Furthermore, 4 of 220 gene co-expression modules tested were significantly enriched for the dystonia-associated genes. The identified modules were derived from the substantia nigra, putamen, frontal cortex, and white matter, and were all significantly enriched for genes associated with synaptic function. Finally, we demonstrate significant enrichments of the heritability of major depressive disorder, obsessive-compulsive disorder and schizophrenia within the putamen and white matter modules, and a significant enrichment of the heritability of Parkinson’s disease within the substantia nigra module. In conclusion, multiple dystonia-associated genes interact and contribute to pathogenesis likely through dysregulation of synaptic signalling in striatal medium spiny neurons, adult nigral dopaminergic neurons and frontal cortical neurons. Furthermore, the enrichment of the heritability of psychiatric disorders in the co-expression modules enriched for dystonia-associated genes indicates that psychiatric symptoms associated with dystonia are likely to be intrinsic to its pathophysiology.

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“…Notably, previous studies have demonstrated the effects of genetic interactions in tissues that seem irrelevant to the phenotypes under investigation [40][41][42][43] . We propose that eQTLs affect metabolism by modulating the expression of genes that encode the protein components (i.e.…”

Section: Discussionmentioning

confidence: 99%

Reconstructing the blood metabolome and genotype using long-range chromatin interactions

Fadason

Schierding

Kolbenev

et al. 2019

Preprint

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AbstractThe mechanisms of metabolism comprise a large number of biochemical pathways with a myriad of poorly characterised genetic influences. In this study, we perform a systematic integration of chromatin interaction (Hi-C), expression quantitative trait loci (eQTL), gene ontology, drug interaction, and literature-supported connections to deconvolute the genetic regulatory influences of 145 blood metabolite-associated single nucleotide polymorphisms (SNPs). We identify 577 genes that are regulated via chromatin looping to 130 distal and proximal SNPs across 48 different human tissues. The affected genes are enriched in categories that include metabolism, enzymes, plasma proteins, disease development, and potential drug targets. These novel SNP-gene-metabolite associations are a valuable resource for understanding the molecular mechanisms guiding pathologic metabolite levels in human tissues, and for further investigation into disease diagnosis and therapy.

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Moving beyond neurons: the role of cell type-specific gene regulation in Parkinson’s disease heritability

Cited by 40 publications

References 73 publications

A single-cell atlas of the human substantia nigra reveals cell-specific pathways associated with neurological disorders

A single-cell atlas of the human substantia nigra reveals cell-specific pathways associated with neurological disorders

Dystonia genes functionally converge in specific neurons and share neurobiology with psychiatric disorders

Reconstructing the blood metabolome and genotype using long-range chromatin interactions

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