Brain-trait-associated variants impact cell-type-specific gene regulation during neurogenesis.
Nil Aygün,Angela L. Elwell,Dan Liang,Michael J. Lafferty,Kerry E. Cheek,Kenan P. Courtney,Jessica T. Mory,Ellie Hadden-Ford,Oleh Krupa,Luis de la Torre-Ubieta,Daniel H. Geschwind,Michael I. Love,Jason L. Stein +12 more
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TLDR
In this paper, the authors map e/sQTLs and allele-specific expression in cultured cells representing two major developmental stages, primary human neural progenitors and their sorted neuronal progeny, identifying numerous loci not detected in either bulk developing cortical wall or adult cortex.Abstract:
Interpretation of the function of non-coding risk loci for neuropsychiatric disorders and brain-relevant traits via gene expression and alternative splicing quantitative trait locus (e/sQTL) analyses is generally performed in bulk post-mortem adult tissue. However, genetic risk loci are enriched in regulatory elements active during neocortical differentiation, and regulatory effects of risk variants may be masked by heterogeneity in bulk tissue. Here, we map e/sQTLs, and allele-specific expression in cultured cells representing two major developmental stages, primary human neural progenitors (n = 85) and their sorted neuronal progeny (n = 74), identifying numerous loci not detected in either bulk developing cortical wall or adult cortex. Using colocalization and genetic imputation via transcriptome-wide association, we uncover cell-type-specific regulatory mechanisms underlying risk for brain-relevant traits that are active during neocortical differentiation. Specifically, we identified a progenitor-specific eQTL for CENPW co-localized with common variant associations for cortical surface area and educational attainment.read more
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Cell-type specific cis-eQTLs in eight brain cell-types identifies novel risk genes for human brain disorders
Julien Bryois,Daniela Calini,W. Macnair,L. Foo,E. Urich,W. Ortmann,V. A. Iglesias,S. Selvaraj,Erik Nutma,Manuel C. Marzin,Sandra Amor,Sandra Amor,Anna Williams,Gonçalo Castelo-Branco,Vilas Menon,P. L. De Jager,Dheeraj Malhotra +16 more
TL;DR: In this paper, the authors performed an eQTL analysis using single nuclei RNA-seq from 196 individuals in eight central nervous system (CNS) cell types and identified 6108 eGenes, a substantial fraction of which show cell-type specific effects, with strongest effects in microglia.
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Bridging the splicing gap in human genetics with long-read RNA sequencing: finding the protein isoform drivers of disease.
TL;DR: An overview of s QTL mapping approaches, the use of long-read sequencing to characterize sQTL effects on isoforms, the linkage of RNA isoforms to protein-level functions, and comment on future directions in the field are provided.
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Accounting for cis-regulatory constraint prioritizes genes likely to affect species-specific traits
TL;DR: In this paper , a simple strategy that leverages population-scale allele-specific RNA-seq data to identify genes that show constrained cis-regulation within species yet show divergence between species was proposed.
Journal ArticleDOI
Natural variation in gene expression and viral susceptibility revealed by neural progenitor cell villages.
Michael F. Wells,James Nemesh,Sulagna Ghosh,Jana M. Mitchell,Max R. Salick,Curtis J. Mello,Daniel Meyer,Olli Pietilainen,Federica Piccioni,Ellen J. Guss,Kavya Raghunathan,Matt Tegtmeyer,Derek C. Hawes,Anna Neumann,Kathleen A. Worringer,Daniel J. Ho,Sravya Kommineni,Karrie Chan,Brant K. Peterson,Joe Raymond,John T. Gold,Marco T Siekmann,Emanuela Zuccaro,Ralda Nehme,Ajamete Kaykas,Kevin Eggan,Steven A. McCarroll +26 more
TL;DR: In this paper , a "cell village" experimental platform was used to analyze genetic, molecular, and phenotypic heterogeneity across neural progenitor cells from 44 human donors cultured in a shared in vitro environment using algorithms (Dropulation and Census-seq) to assign cells and phenotypes to individual donors.
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Cellular Genome-wide Association Study Identifies Common Genetic Variation Influencing Lithium-Induced Neural Progenitor Proliferation
TL;DR: In this paper , the authors performed a genome-wide association study to identify common genetic variants that influence lithium-induced neural progenitor cell proliferation and found that common genetic variation was necessary for the full proliferation-stimulating effects of lithium.
References
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Yoav Benjamini,Yosef Hochberg +1 more
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Regression Shrinkage and Selection via the Lasso
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STAR: ultrafast universal RNA-seq aligner
Alexander Dobin,Carrie A. Davis,Felix Schlesinger,Jorg Drenkow,Chris Zaleski,Sonali Jha,Philippe Batut,Mark Chaisson,Thomas R. Gingeras +8 more
TL;DR: The Spliced Transcripts Alignment to a Reference (STAR) software based on a previously undescribed RNA-seq alignment algorithm that uses sequential maximum mappable seed search in uncompressed suffix arrays followed by seed clustering and stitching procedure outperforms other aligners by a factor of >50 in mapping speed.
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limma powers differential expression analyses for RNA-sequencing and microarray studies
Matthew E. Ritchie,Belinda Phipson,Di Wu,Yifang Hu,Charity W. Law,Wei Shi,Gordon K. Smyth,Gordon K. Smyth +7 more
TL;DR: The philosophy and design of the limma package is reviewed, summarizing both new and historical features, with an emphasis on recent enhancements and features that have not been previously described.