PT  - JOURNAL ARTICLE
AU  - Jeremy Schwartzentruber
AU  - Stefanie Foskolou
AU  - Helena Kilpinen
AU  - Julia Rodrigues
AU  - Kaur Alasoo
AU  - Andrew J Knights
AU  - Minal Patel
AU  - Angela Goncalves
AU  - Rita Ferreira
AU  - Caroline Louise Benn
AU  - Anna Wilbrey
AU  - Magda Bictash
AU  - Emma Impey
AU  - Lishuang Cao
AU  - Sergio Lainez
AU  - Alexandre Julien Loucif
AU  - Paul John Whiting
AU  - HIPSCI Consortium (www.hipsci.org)
AU  - Alex Gutteridge
AU  - Daniel J Gaffney
TI  - Molecular and functional variation in iPSC-derived sensory neurons
AID  - 10.1101/095943
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 095943
4099  - http://biorxiv.org/content/early/2017/01/06/095943.short
4100  - http://biorxiv.org/content/early/2017/01/06/095943.full
AB  - Induced pluripotent stem cells (iPSCs), and cells derived from them, have become key tools to model biological processes and disease mechanisms, particularly in cell types such as neurons that are difficult to access from living donors. Here, we present the first map of regulatory variants in an iPSC-derived cell type. To investigate genetic contributions to human sensory function, we performed 123 differentiations of iPSCs from 103 unique donors to a sensory neuronal fate, and measured gene expression, chromatin accessibility, and neuronal excitability. Compared with primary dorsal root ganglion, where sensory nerves collect near the spinal cord, gene expression was more variable across iPSC-derived neuronal cultures, particularly in genes related to differentiation and nervous system development. Single cell RNA-sequencing revealed that although the majority of cells are neuronal and express the expected marker genes, a substantial fraction have a fibroblast-like expression profile. By applying an allele-specific method we identify 3,778 quantitative trait loci influencing gene expression, 6,318 for chromatin accessibility, and 2,097 for RNA splicing at FDR 10%. A number of these overlap with common disease associations, and suggest candidate causal variants and target genes. These include known causal variants at SNCA for Parkinson’s disease and TNFRSF1A for multiple sclerosis, as well as new candidates for migraine, Parkinson’s disease, and schizophrenia.