1. Population-scale proteome variation in human induced pluripotent stem cells
- Author
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Mirauta, Bogdan Andrei, Seaton, Daniel D, Bensaddek, Dalila, Brenes, Alejandro, Bonder, Marc Jan, Kilpinen, Helena, Agu, Chukwuma A, Alderton, Alex, Danecek, Petr, Denton, Rachel, Durbin, Richard, Gaffney, Daniel J, Goncalves, Angela, Halai, Reena, Harper, Sarah, Kirton, Christopher M, Kolb-Kokocinski, Anja, Leha, Andreas, McCarthy, Shane A, Memari, Yasin, Patel, Minal, Birney, Ewan, Casale, Francesco Paolo, Clarke, Laura, Harrison, Peter W, Streeter, Ian, Denovi, Davide, Stegle, Oliver, Lamond, Angus I, Meleckyte, Ruta, Moens, Natalie, Watt, Fiona M, Ouwehand, Willem H, Beales, Philip, Mirauta, Bogdan Andrei [0000-0002-9733-292X], Bonder, Marc Jan [0000-0002-8431-3180], Kilpinen, Helena [0000-0001-6692-6154], Stegle, Oliver [0000-0002-8818-7193], Lamond, Angus I [0000-0001-6204-6045], Apollo - University of Cambridge Repository, and Helsinki Institute of Life Science HiLIFE
- Subjects
Male ,Proteomics ,Proteome ,Genome-wide association study ,VARIANTS ,Transcriptome ,0302 clinical medicine ,SCHIZOPHRENIA ,Human proteome project ,genetics ,Disease ,Biology (General) ,Induced pluripotent stem cell ,Child ,GENE-EXPRESSION ,0303 health sciences ,education.field_of_study ,Drug discovery ,General Neuroscience ,General Medicine ,Middle Aged ,Phenotype ,Child, Preschool ,Medicine ,ABUNDANCE ,Female ,Research Article ,Adult ,Adolescent ,Genotype ,QH301-705.5 ,induced pluripotent stem cells ,Science ,Population ,Quantitative Trait Loci ,deleterious variants ,Genomics ,Computational biology ,Quantitative trait locus ,Biology ,General Biochemistry, Genetics and Molecular Biology ,DIFFERENTIAL EXPRESSION ,03 medical and health sciences ,Young Adult ,RESOURCE ,REVEALS ,genomics ,Humans ,human ,RNA, Messenger ,education ,030304 developmental biology ,Aged ,IDENTIFICATION ,General Immunology and Microbiology ,Infant, Newborn ,Genetic Variation ,Infant ,Genetics and Genomics ,QUANTIFICATION ,Genetics, Population ,REGULATORY VARIATION ,3111 Biomedicine ,030217 neurology & neurosurgery - Abstract
Human disease phenotypes are driven primarily by alterations in protein expression and/or function. To date, relatively little is known about the variability of the human proteome in populations and how this relates to variability in mRNA expression and to disease loci. Here, we present the first comprehensive proteomic analysis of human induced pluripotent stem cells (iPSC), a key cell type for disease modelling, analysing 202 iPSC lines derived from 151 donors, with integrated transcriptome and genomic sequence data from the same lines. We characterised the major genetic and non-genetic determinants of proteome variation across iPSC lines and assessed key regulatory mechanisms affecting variation in protein abundance. We identified 654 protein quantitative trait loci (pQTLs) in iPSCs, including disease-linked variants in protein-coding sequences and variants with trans regulatory effects. These include pQTL linked to GWAS variants that cannot be detected at the mRNA level, highlighting the utility of dissecting pQTL at peptide level resolution.
- Published
- 2020