Cargando…

Evaluating the Contribution of Cell Type–Specific Alternative Splicing to Variation in Lipid Levels

Genome-wide association studies have identified hundreds of loci associated with lipid levels. However, the genetic mechanisms underlying most of these loci are not well-understood. Recent work indicates that changes in the abundance of alternatively spliced transcripts contribute to complex trait v...

Descripción completa

Detalles Bibliográficos
Autores principales: Gawronski, Katerina A.B., Bone, William P., Park, YoSon, Pashos, Evanthia E., Wenz, Brandon M., Dudek, Max F., Wang, Xiao, Yang, Wenli, Rader, Daniel J., Musunuru, Kiran, Voight, Benjamin F., Brown, Christopher D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Lippincott Williams & Wilkins 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10284136/
https://www.ncbi.nlm.nih.gov/pubmed/37165871
http://dx.doi.org/10.1161/CIRCGEN.120.003249
_version_ 1785061342222221312
author Gawronski, Katerina A.B.
Bone, William P.
Park, YoSon
Pashos, Evanthia E.
Wenz, Brandon M.
Dudek, Max F.
Wang, Xiao
Yang, Wenli
Rader, Daniel J.
Musunuru, Kiran
Voight, Benjamin F.
Brown, Christopher D.
author_facet Gawronski, Katerina A.B.
Bone, William P.
Park, YoSon
Pashos, Evanthia E.
Wenz, Brandon M.
Dudek, Max F.
Wang, Xiao
Yang, Wenli
Rader, Daniel J.
Musunuru, Kiran
Voight, Benjamin F.
Brown, Christopher D.
author_sort Gawronski, Katerina A.B.
collection PubMed
description Genome-wide association studies have identified hundreds of loci associated with lipid levels. However, the genetic mechanisms underlying most of these loci are not well-understood. Recent work indicates that changes in the abundance of alternatively spliced transcripts contribute to complex trait variation. Consequently, identifying genetic loci that associate with alternative splicing in disease-relevant cell types and determining the degree to which these loci are informative for lipid biology is of broad interest. METHODS: We analyze gene splicing in 83 sample-matched induced pluripotent stem cell (iPSC) and hepatocyte-like cell lines (n=166), as well as in an independent collection of primary liver tissues (n=96) to perform discovery of splicing quantitative trait loci (sQTLs). RESULTS: We observe that transcript splicing is highly cell type specific, and the genes that are differentially spliced between iPSCs and hepatocyte-like cells are enriched for metabolism pathway annotations. We identify 1384 hepatocyte-like cell sQTLs and 1455 iPSC sQTLs at a false discovery rate of <5% and find that sQTLs are often shared across cell types. To evaluate the contribution of sQTLs to variation in lipid levels, we conduct colocalization analysis using lipid genome-wide association data. We identify 19 lipid-associated loci that colocalize either with an hepatocyte-like cell expression quantitative trait locus or sQTL. Only 2 loci colocalize with both a sQTL and expression quantitative trait locus, indicating that sQTLs contribute information about genome-wide association studies loci that cannot be obtained by analysis of steady-state gene expression alone. CONCLUSIONS: These results provide an important foundation for future efforts that use iPSC and iPSC-derived cells to evaluate genetic mechanisms influencing both cardiovascular disease risk and complex traits in general.
format Online
Article
Text
id pubmed-10284136
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Lippincott Williams & Wilkins
record_format MEDLINE/PubMed
spelling pubmed-102841362023-06-22 Evaluating the Contribution of Cell Type–Specific Alternative Splicing to Variation in Lipid Levels Gawronski, Katerina A.B. Bone, William P. Park, YoSon Pashos, Evanthia E. Wenz, Brandon M. Dudek, Max F. Wang, Xiao Yang, Wenli Rader, Daniel J. Musunuru, Kiran Voight, Benjamin F. Brown, Christopher D. Circ Genom Precis Med Original Articles Genome-wide association studies have identified hundreds of loci associated with lipid levels. However, the genetic mechanisms underlying most of these loci are not well-understood. Recent work indicates that changes in the abundance of alternatively spliced transcripts contribute to complex trait variation. Consequently, identifying genetic loci that associate with alternative splicing in disease-relevant cell types and determining the degree to which these loci are informative for lipid biology is of broad interest. METHODS: We analyze gene splicing in 83 sample-matched induced pluripotent stem cell (iPSC) and hepatocyte-like cell lines (n=166), as well as in an independent collection of primary liver tissues (n=96) to perform discovery of splicing quantitative trait loci (sQTLs). RESULTS: We observe that transcript splicing is highly cell type specific, and the genes that are differentially spliced between iPSCs and hepatocyte-like cells are enriched for metabolism pathway annotations. We identify 1384 hepatocyte-like cell sQTLs and 1455 iPSC sQTLs at a false discovery rate of <5% and find that sQTLs are often shared across cell types. To evaluate the contribution of sQTLs to variation in lipid levels, we conduct colocalization analysis using lipid genome-wide association data. We identify 19 lipid-associated loci that colocalize either with an hepatocyte-like cell expression quantitative trait locus or sQTL. Only 2 loci colocalize with both a sQTL and expression quantitative trait locus, indicating that sQTLs contribute information about genome-wide association studies loci that cannot be obtained by analysis of steady-state gene expression alone. CONCLUSIONS: These results provide an important foundation for future efforts that use iPSC and iPSC-derived cells to evaluate genetic mechanisms influencing both cardiovascular disease risk and complex traits in general. Lippincott Williams & Wilkins 2023-05-11 2023-06 /pmc/articles/PMC10284136/ /pubmed/37165871 http://dx.doi.org/10.1161/CIRCGEN.120.003249 Text en © 2023 The Authors. https://creativecommons.org/licenses/by/4.0/Circulation: Genomic and Precision Medicine is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.
spellingShingle Original Articles
Gawronski, Katerina A.B.
Bone, William P.
Park, YoSon
Pashos, Evanthia E.
Wenz, Brandon M.
Dudek, Max F.
Wang, Xiao
Yang, Wenli
Rader, Daniel J.
Musunuru, Kiran
Voight, Benjamin F.
Brown, Christopher D.
Evaluating the Contribution of Cell Type–Specific Alternative Splicing to Variation in Lipid Levels
title Evaluating the Contribution of Cell Type–Specific Alternative Splicing to Variation in Lipid Levels
title_full Evaluating the Contribution of Cell Type–Specific Alternative Splicing to Variation in Lipid Levels
title_fullStr Evaluating the Contribution of Cell Type–Specific Alternative Splicing to Variation in Lipid Levels
title_full_unstemmed Evaluating the Contribution of Cell Type–Specific Alternative Splicing to Variation in Lipid Levels
title_short Evaluating the Contribution of Cell Type–Specific Alternative Splicing to Variation in Lipid Levels
title_sort evaluating the contribution of cell type–specific alternative splicing to variation in lipid levels
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10284136/
https://www.ncbi.nlm.nih.gov/pubmed/37165871
http://dx.doi.org/10.1161/CIRCGEN.120.003249
work_keys_str_mv AT gawronskikaterinaab evaluatingthecontributionofcelltypespecificalternativesplicingtovariationinlipidlevels
AT bonewilliamp evaluatingthecontributionofcelltypespecificalternativesplicingtovariationinlipidlevels
AT parkyoson evaluatingthecontributionofcelltypespecificalternativesplicingtovariationinlipidlevels
AT pashosevanthiae evaluatingthecontributionofcelltypespecificalternativesplicingtovariationinlipidlevels
AT wenzbrandonm evaluatingthecontributionofcelltypespecificalternativesplicingtovariationinlipidlevels
AT dudekmaxf evaluatingthecontributionofcelltypespecificalternativesplicingtovariationinlipidlevels
AT wangxiao evaluatingthecontributionofcelltypespecificalternativesplicingtovariationinlipidlevels
AT yangwenli evaluatingthecontributionofcelltypespecificalternativesplicingtovariationinlipidlevels
AT raderdanielj evaluatingthecontributionofcelltypespecificalternativesplicingtovariationinlipidlevels
AT musunurukiran evaluatingthecontributionofcelltypespecificalternativesplicingtovariationinlipidlevels
AT voightbenjaminf evaluatingthecontributionofcelltypespecificalternativesplicingtovariationinlipidlevels
AT brownchristopherd evaluatingthecontributionofcelltypespecificalternativesplicingtovariationinlipidlevels