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Systematic visualisation of molecular QTLs reveals variant mechanisms at GWAS loci
Splicing quantitative trait loci (QTLs) have been implicated as a common mechanism underlying complex trait associations. However, utilising splicing QTLs in target discovery and prioritisation has been challenging due to extensive data normalisation which often renders the direction of the genetic...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10104061/ https://www.ncbi.nlm.nih.gov/pubmed/37066341 http://dx.doi.org/10.1101/2023.04.06.535816 |
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author | Kerimov, Nurlan Tambets, Ralf Hayhurst, James D. Rahu, Ida Kolberg, Peep Raudvere, Uku Kuzmin, Ivan Chowdhary, Anshika Vija, Andreas Teras, Hans J. Kanai, Masahiro Ulirsch, Jacob Ryten, Mina Hardy, John Guelfi, Sebastian Trabzuni, Daniah Kim-Hellmuth, Sarah Rayner, Will Finucane, Hilary Peterson, Hedi Mosaku, Abayomi Parkinson, Helen Alasoo, Kaur |
author_facet | Kerimov, Nurlan Tambets, Ralf Hayhurst, James D. Rahu, Ida Kolberg, Peep Raudvere, Uku Kuzmin, Ivan Chowdhary, Anshika Vija, Andreas Teras, Hans J. Kanai, Masahiro Ulirsch, Jacob Ryten, Mina Hardy, John Guelfi, Sebastian Trabzuni, Daniah Kim-Hellmuth, Sarah Rayner, Will Finucane, Hilary Peterson, Hedi Mosaku, Abayomi Parkinson, Helen Alasoo, Kaur |
author_sort | Kerimov, Nurlan |
collection | PubMed |
description | Splicing quantitative trait loci (QTLs) have been implicated as a common mechanism underlying complex trait associations. However, utilising splicing QTLs in target discovery and prioritisation has been challenging due to extensive data normalisation which often renders the direction of the genetic effect as well as its magnitude difficult to interpret. This is further complicated by the fact that strong expression QTLs often manifest as weak splicing QTLs and vice versa, making it difficult to uniquely identify the underlying molecular mechanism at each locus. We find that these ambiguities can be mitigated by visualising the association between the genotype and average RNA sequencing read coverage in the region. Here, we generate these QTL coverage plots for 1.7 million molecular QTL associations in the eQTL Catalogue identified with five quantification methods. We illustrate the utility of these QTL coverage plots by performing colocalisation between vitamin D levels in the UK Biobank and all molecular QTLs in the eQTL Catalogue. We find that while visually confirmed splicing QTLs explain just 6/53 of the colocalising signals, they are significantly less pleiotropic than eQTLs and identify a prioritised causal gene in 4/6 cases. All our association summary statistics and QTL coverage plots are freely available at https://www.ebi.ac.uk/eqtl/. |
format | Online Article Text |
id | pubmed-10104061 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Cold Spring Harbor Laboratory |
record_format | MEDLINE/PubMed |
spelling | pubmed-101040612023-04-15 Systematic visualisation of molecular QTLs reveals variant mechanisms at GWAS loci Kerimov, Nurlan Tambets, Ralf Hayhurst, James D. Rahu, Ida Kolberg, Peep Raudvere, Uku Kuzmin, Ivan Chowdhary, Anshika Vija, Andreas Teras, Hans J. Kanai, Masahiro Ulirsch, Jacob Ryten, Mina Hardy, John Guelfi, Sebastian Trabzuni, Daniah Kim-Hellmuth, Sarah Rayner, Will Finucane, Hilary Peterson, Hedi Mosaku, Abayomi Parkinson, Helen Alasoo, Kaur bioRxiv Article Splicing quantitative trait loci (QTLs) have been implicated as a common mechanism underlying complex trait associations. However, utilising splicing QTLs in target discovery and prioritisation has been challenging due to extensive data normalisation which often renders the direction of the genetic effect as well as its magnitude difficult to interpret. This is further complicated by the fact that strong expression QTLs often manifest as weak splicing QTLs and vice versa, making it difficult to uniquely identify the underlying molecular mechanism at each locus. We find that these ambiguities can be mitigated by visualising the association between the genotype and average RNA sequencing read coverage in the region. Here, we generate these QTL coverage plots for 1.7 million molecular QTL associations in the eQTL Catalogue identified with five quantification methods. We illustrate the utility of these QTL coverage plots by performing colocalisation between vitamin D levels in the UK Biobank and all molecular QTLs in the eQTL Catalogue. We find that while visually confirmed splicing QTLs explain just 6/53 of the colocalising signals, they are significantly less pleiotropic than eQTLs and identify a prioritised causal gene in 4/6 cases. All our association summary statistics and QTL coverage plots are freely available at https://www.ebi.ac.uk/eqtl/. Cold Spring Harbor Laboratory 2023-04-07 /pmc/articles/PMC10104061/ /pubmed/37066341 http://dx.doi.org/10.1101/2023.04.06.535816 Text en https://creativecommons.org/licenses/by/4.0/This work is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/) , which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. |
spellingShingle | Article Kerimov, Nurlan Tambets, Ralf Hayhurst, James D. Rahu, Ida Kolberg, Peep Raudvere, Uku Kuzmin, Ivan Chowdhary, Anshika Vija, Andreas Teras, Hans J. Kanai, Masahiro Ulirsch, Jacob Ryten, Mina Hardy, John Guelfi, Sebastian Trabzuni, Daniah Kim-Hellmuth, Sarah Rayner, Will Finucane, Hilary Peterson, Hedi Mosaku, Abayomi Parkinson, Helen Alasoo, Kaur Systematic visualisation of molecular QTLs reveals variant mechanisms at GWAS loci |
title | Systematic visualisation of molecular QTLs reveals variant mechanisms at GWAS loci |
title_full | Systematic visualisation of molecular QTLs reveals variant mechanisms at GWAS loci |
title_fullStr | Systematic visualisation of molecular QTLs reveals variant mechanisms at GWAS loci |
title_full_unstemmed | Systematic visualisation of molecular QTLs reveals variant mechanisms at GWAS loci |
title_short | Systematic visualisation of molecular QTLs reveals variant mechanisms at GWAS loci |
title_sort | systematic visualisation of molecular qtls reveals variant mechanisms at gwas loci |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10104061/ https://www.ncbi.nlm.nih.gov/pubmed/37066341 http://dx.doi.org/10.1101/2023.04.06.535816 |
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