02457nas a2200505   4500000000100000000000100001008004100002260001200043653002500055653002500080653003800105653001100143653003500154653001700189653002100206653002800227653004700255653001300302653002700315653002500342653001800367100001700385700002100402700002100423700002300444700001800467700001900485700001600504700001800520700002000538700002000558700001600578700002000594700002600614700002200640700002000662700002200682700002200704700001800726245009400744300001200838490000700850520108000857022001401937       2021                            d  c2021-0310aCell Differentiation10aDopaminergic Neurons10aGenetic Predisposition to Disease10aHumans10ainduced pluripotent stem cells10aNeurogenesis10aOxidative Stress10aQuantitative Trait Loci10aReceptor, Fibroblast Growth Factor, Type 110aRotenone10aSequence Analysis, RNA10aSingle-Cell Analysis10aTranscriptome1 aJulie Jerber1 aDaniel D. Seaton1 aAnna S. E. Cuomo1 aNatsuhiko Kumasaka1 aJames Haldane1 aJuliette Steer1 aMinal Patel1 aDaniel Pearce1 aMalin Andersson1 aMarc Jan Bonder1 aEd Mountjoy1 aMaya Ghoussaini1 aMadeline A. Lancaster1 aHipSci Consortium1 aJohn C. Marioni1 aFlorian T. Merkle1 aDaniel J. Gaffney1 aOliver Stegle00aPopulation-scale single-cell RNA-seq profiling across dopaminergic neuron differentiation  a304-3120 v533 aStudying 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.  a1546-1718