Genetic effects on promoter usage are highly context-specific and contribute to complex traits
Genetic variants regulating RNA splicing and transcript usage have been implicated in both common and rare diseases. Although transcript usage quantitative trait loci (tuQTLs) have been mapped across multiple cell types and contexts, it is challenging to distinguish between the main molecular mechan...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2019-01-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/41673 |
| _version_ | 1828221632150241280 |
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| author | Kaur Alasoo Julia Rodrigues John Danesh Daniel F Freitag Dirk S Paul Daniel J Gaffney |
| author_facet | Kaur Alasoo Julia Rodrigues John Danesh Daniel F Freitag Dirk S Paul Daniel J Gaffney |
| author_sort | Kaur Alasoo |
| collection | DOAJ |
| description | Genetic variants regulating RNA splicing and transcript usage have been implicated in both common and rare diseases. Although transcript usage quantitative trait loci (tuQTLs) have been mapped across multiple cell types and contexts, it is challenging to distinguish between the main molecular mechanisms controlling transcript usage: promoter choice, splicing and 3ʹ end choice. Here, we analysed RNA-seq data from human macrophages exposed to three inflammatory and one metabolic stimulus. In addition to conventional gene-level and transcript-level analyses, we also directly quantified promoter usage, splicing and 3ʹ end usage. We found that promoters, splicing and 3ʹ ends were predominantly controlled by independent genetic variants enriched in distinct genomic features. Promoter usage QTLs were also 50% more likely to be context-specific than other tuQTLs and constituted 25% of the transcript-level colocalisations with complex traits. Thus, promoter usage might be an underappreciated molecular mechanism mediating complex trait associations in a context-specific manner. |
| first_indexed | 2024-04-12T16:43:57Z |
| format | Article |
| id | doaj.art-2751f30f15a54b26b8e5447bf343ad5b |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T16:43:57Z |
| publishDate | 2019-01-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-2751f30f15a54b26b8e5447bf343ad5b2022-12-22T03:24:39ZengeLife Sciences Publications LtdeLife2050-084X2019-01-01810.7554/eLife.41673Genetic effects on promoter usage are highly context-specific and contribute to complex traitsKaur Alasoo0https://orcid.org/0000-0002-1761-8881Julia Rodrigues1John Danesh2Daniel F Freitag3Dirk S Paul4https://orcid.org/0000-0002-8230-0116Daniel J Gaffney5Institute of Computer Science, University of Tartu, Tartu, Estonia; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, United KingdomWellcome Sanger Institute, Wellcome Genome Campus, Hinxton, United KingdomWellcome Sanger Institute, Wellcome Genome Campus, Hinxton, United Kingdom; BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom; British Heart Foundation Centre of Excellence, Division of Cardiovascular Medicine, Addenbrooke’s Hospital, Cambridge, United Kingdom; National Institute for Health Research Blood and Transplant Unit (NIHR BTRU) in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United KingdomWellcome Sanger Institute, Wellcome Genome Campus, Hinxton, United Kingdom; British Heart Foundation Centre of Excellence, Division of Cardiovascular Medicine, Addenbrooke’s Hospital, Cambridge, United KingdomWellcome Sanger Institute, Wellcome Genome Campus, Hinxton, United Kingdom; British Heart Foundation Centre of Excellence, Division of Cardiovascular Medicine, Addenbrooke’s Hospital, Cambridge, United KingdomWellcome Sanger Institute, Wellcome Genome Campus, Hinxton, United KingdomGenetic variants regulating RNA splicing and transcript usage have been implicated in both common and rare diseases. Although transcript usage quantitative trait loci (tuQTLs) have been mapped across multiple cell types and contexts, it is challenging to distinguish between the main molecular mechanisms controlling transcript usage: promoter choice, splicing and 3ʹ end choice. Here, we analysed RNA-seq data from human macrophages exposed to three inflammatory and one metabolic stimulus. In addition to conventional gene-level and transcript-level analyses, we also directly quantified promoter usage, splicing and 3ʹ end usage. We found that promoters, splicing and 3ʹ ends were predominantly controlled by independent genetic variants enriched in distinct genomic features. Promoter usage QTLs were also 50% more likely to be context-specific than other tuQTLs and constituted 25% of the transcript-level colocalisations with complex traits. Thus, promoter usage might be an underappreciated molecular mechanism mediating complex trait associations in a context-specific manner.https://elifesciences.org/articles/41673splicingRNA-seqmacrophagesgeneticstranscription |
| spellingShingle | Kaur Alasoo Julia Rodrigues John Danesh Daniel F Freitag Dirk S Paul Daniel J Gaffney Genetic effects on promoter usage are highly context-specific and contribute to complex traits eLife splicing RNA-seq macrophages genetics transcription |
| title | Genetic effects on promoter usage are highly context-specific and contribute to complex traits |
| title_full | Genetic effects on promoter usage are highly context-specific and contribute to complex traits |
| title_fullStr | Genetic effects on promoter usage are highly context-specific and contribute to complex traits |
| title_full_unstemmed | Genetic effects on promoter usage are highly context-specific and contribute to complex traits |
| title_short | Genetic effects on promoter usage are highly context-specific and contribute to complex traits |
| title_sort | genetic effects on promoter usage are highly context specific and contribute to complex traits |
| topic | splicing RNA-seq macrophages genetics transcription |
| url | https://elifesciences.org/articles/41673 |
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