TY - JOUR
KW - Cell Differentiation
KW - Dopaminergic Neurons
KW - Genetic Predisposition to Disease
KW - Humans
KW - induced pluripotent stem cells
KW - Neurogenesis
KW - Oxidative Stress
KW - Quantitative Trait Loci
KW - Receptor, Fibroblast Growth Factor, Type 1
KW - Rotenone
KW - Sequence Analysis, RNA
KW - Single-Cell Analysis
KW - Transcriptome
AU - Julie Jerber
AU - Daniel D. Seaton
AU - Anna S. E. Cuomo
AU - Natsuhiko Kumasaka
AU - James Haldane
AU - Juliette Steer
AU - Minal Patel
AU - Daniel Pearce
AU - Malin Andersson
AU - Marc Jan Bonder
AU - Ed Mountjoy
AU - Maya Ghoussaini
AU - Madeline A. Lancaster
AU - HipSci Consortium
AU - John C. Marioni
AU - Florian T. Merkle
AU - Daniel J. Gaffney
AU - Oliver Stegle
AB - Studying the function of common genetic variants in primary human tissues and during development is challenging. To address this, we use an efficient multiplexing strategy to differentiate 215 human induced pluripotent stem cell (iPSC) lines toward a midbrain neural fate, including dopaminergic neurons, and use single-cell RNA sequencing (scRNA-seq) to profile over 1 million cells across three differentiation time points. The proportion of neurons produced by each cell line is highly reproducible and is predictable by robust molecular markers expressed in pluripotent cells. Expression quantitative trait loci (eQTL) were characterized at different stages of neuronal development and in response to rotenone-induced oxidative stress. Of these, 1,284 eQTL colocalize with known neurological trait risk loci, and 46% are not found in the Genotype-Tissue Expression (GTEx) catalog. Our study illustrates how coupling scRNA-seq with long-term iPSC differentiation enables mechanistic studies of human trait-associated genetic variants in otherwise inaccessible cell states.
BT - Nature Genetics
DA - 2021-03
DO - 10.1038/s41588-021-00801-6
IS - 3
LA - eng
N2 - Studying the function of common genetic variants in primary human tissues and during development is challenging. To address this, we use an efficient multiplexing strategy to differentiate 215 human induced pluripotent stem cell (iPSC) lines toward a midbrain neural fate, including dopaminergic neurons, and use single-cell RNA sequencing (scRNA-seq) to profile over 1 million cells across three differentiation time points. The proportion of neurons produced by each cell line is highly reproducible and is predictable by robust molecular markers expressed in pluripotent cells. Expression quantitative trait loci (eQTL) were characterized at different stages of neuronal development and in response to rotenone-induced oxidative stress. Of these, 1,284 eQTL colocalize with known neurological trait risk loci, and 46% are not found in the Genotype-Tissue Expression (GTEx) catalog. Our study illustrates how coupling scRNA-seq with long-term iPSC differentiation enables mechanistic studies of human trait-associated genetic variants in otherwise inaccessible cell states.
PY - 2021
SP - 304
EP - 312
T2 - Nature Genetics
TI - Population-scale single-cell RNA-seq profiling across dopaminergic neuron differentiation
VL - 53
SN - 1546-1718
ER -