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Integrative analysis of gene expression, DNA methylation, physiological traits, and genetic variation in human skeletal muscle

We integrate comeasured gene expression and DNA methylation (DNAme) in 265 human skeletal muscle biopsies from the FUSION study with >7 million genetic variants and eight physiological traits: height, waist, weight, waist–hip ratio, body mass index, fasting serum insulin, fasting plasma glucose,...

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Autores principales: Taylor, D. Leland, Jackson, Anne U., Narisu, Narisu, Hemani, Gibran, Erdos, Michael R., Chines, Peter S., Swift, Amy, Idol, Jackie, Didion, John P., Welch, Ryan P., Kinnunen, Leena, Saramies, Jouko, Lakka, Timo A., Laakso, Markku, Tuomilehto, Jaakko, Parker, Stephen C. J., Koistinen, Heikki A., Davey Smith, George, Boehnke, Michael, Scott, Laura J., Birney, Ewan, Collins, Francis S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561151/
https://www.ncbi.nlm.nih.gov/pubmed/31076557
http://dx.doi.org/10.1073/pnas.1814263116
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author Taylor, D. Leland
Jackson, Anne U.
Narisu, Narisu
Hemani, Gibran
Erdos, Michael R.
Chines, Peter S.
Swift, Amy
Idol, Jackie
Didion, John P.
Welch, Ryan P.
Kinnunen, Leena
Saramies, Jouko
Lakka, Timo A.
Laakso, Markku
Tuomilehto, Jaakko
Parker, Stephen C. J.
Koistinen, Heikki A.
Davey Smith, George
Boehnke, Michael
Scott, Laura J.
Birney, Ewan
Collins, Francis S.
author_facet Taylor, D. Leland
Jackson, Anne U.
Narisu, Narisu
Hemani, Gibran
Erdos, Michael R.
Chines, Peter S.
Swift, Amy
Idol, Jackie
Didion, John P.
Welch, Ryan P.
Kinnunen, Leena
Saramies, Jouko
Lakka, Timo A.
Laakso, Markku
Tuomilehto, Jaakko
Parker, Stephen C. J.
Koistinen, Heikki A.
Davey Smith, George
Boehnke, Michael
Scott, Laura J.
Birney, Ewan
Collins, Francis S.
author_sort Taylor, D. Leland
collection PubMed
description We integrate comeasured gene expression and DNA methylation (DNAme) in 265 human skeletal muscle biopsies from the FUSION study with >7 million genetic variants and eight physiological traits: height, waist, weight, waist–hip ratio, body mass index, fasting serum insulin, fasting plasma glucose, and type 2 diabetes. We find hundreds of genes and DNAme sites associated with fasting insulin, waist, and body mass index, as well as thousands of DNAme sites associated with gene expression (eQTM). We find that controlling for heterogeneity in tissue/muscle fiber type reduces the number of physiological trait associations, and that long-range eQTMs (>1 Mb) are reduced when controlling for tissue/muscle fiber type or latent factors. We map genetic regulators (quantitative trait loci; QTLs) of expression (eQTLs) and DNAme (mQTLs). Using Mendelian randomization (MR) and mediation techniques, we leverage these genetic maps to predict 213 causal relationships between expression and DNAme, approximately two-thirds of which predict methylation to causally influence expression. We use MR to integrate FUSION mQTLs, FUSION eQTLs, and GTEx eQTLs for 48 tissues with genetic associations for 534 diseases and quantitative traits. We identify hundreds of genes and thousands of DNAme sites that may drive the reported disease/quantitative trait genetic associations. We identify 300 gene expression MR associations that are present in both FUSION and GTEx skeletal muscle and that show stronger evidence of MR association in skeletal muscle than other tissues, which may partially reflect differences in power across tissues. As one example, we find that increased RXRA muscle expression may decrease lean tissue mass.
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spelling pubmed-65611512019-06-17 Integrative analysis of gene expression, DNA methylation, physiological traits, and genetic variation in human skeletal muscle Taylor, D. Leland Jackson, Anne U. Narisu, Narisu Hemani, Gibran Erdos, Michael R. Chines, Peter S. Swift, Amy Idol, Jackie Didion, John P. Welch, Ryan P. Kinnunen, Leena Saramies, Jouko Lakka, Timo A. Laakso, Markku Tuomilehto, Jaakko Parker, Stephen C. J. Koistinen, Heikki A. Davey Smith, George Boehnke, Michael Scott, Laura J. Birney, Ewan Collins, Francis S. Proc Natl Acad Sci U S A Biological Sciences We integrate comeasured gene expression and DNA methylation (DNAme) in 265 human skeletal muscle biopsies from the FUSION study with >7 million genetic variants and eight physiological traits: height, waist, weight, waist–hip ratio, body mass index, fasting serum insulin, fasting plasma glucose, and type 2 diabetes. We find hundreds of genes and DNAme sites associated with fasting insulin, waist, and body mass index, as well as thousands of DNAme sites associated with gene expression (eQTM). We find that controlling for heterogeneity in tissue/muscle fiber type reduces the number of physiological trait associations, and that long-range eQTMs (>1 Mb) are reduced when controlling for tissue/muscle fiber type or latent factors. We map genetic regulators (quantitative trait loci; QTLs) of expression (eQTLs) and DNAme (mQTLs). Using Mendelian randomization (MR) and mediation techniques, we leverage these genetic maps to predict 213 causal relationships between expression and DNAme, approximately two-thirds of which predict methylation to causally influence expression. We use MR to integrate FUSION mQTLs, FUSION eQTLs, and GTEx eQTLs for 48 tissues with genetic associations for 534 diseases and quantitative traits. We identify hundreds of genes and thousands of DNAme sites that may drive the reported disease/quantitative trait genetic associations. We identify 300 gene expression MR associations that are present in both FUSION and GTEx skeletal muscle and that show stronger evidence of MR association in skeletal muscle than other tissues, which may partially reflect differences in power across tissues. As one example, we find that increased RXRA muscle expression may decrease lean tissue mass. National Academy of Sciences 2019-05-28 2019-05-10 /pmc/articles/PMC6561151/ /pubmed/31076557 http://dx.doi.org/10.1073/pnas.1814263116 Text en Copyright © 2019 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Taylor, D. Leland
Jackson, Anne U.
Narisu, Narisu
Hemani, Gibran
Erdos, Michael R.
Chines, Peter S.
Swift, Amy
Idol, Jackie
Didion, John P.
Welch, Ryan P.
Kinnunen, Leena
Saramies, Jouko
Lakka, Timo A.
Laakso, Markku
Tuomilehto, Jaakko
Parker, Stephen C. J.
Koistinen, Heikki A.
Davey Smith, George
Boehnke, Michael
Scott, Laura J.
Birney, Ewan
Collins, Francis S.
Integrative analysis of gene expression, DNA methylation, physiological traits, and genetic variation in human skeletal muscle
title Integrative analysis of gene expression, DNA methylation, physiological traits, and genetic variation in human skeletal muscle
title_full Integrative analysis of gene expression, DNA methylation, physiological traits, and genetic variation in human skeletal muscle
title_fullStr Integrative analysis of gene expression, DNA methylation, physiological traits, and genetic variation in human skeletal muscle
title_full_unstemmed Integrative analysis of gene expression, DNA methylation, physiological traits, and genetic variation in human skeletal muscle
title_short Integrative analysis of gene expression, DNA methylation, physiological traits, and genetic variation in human skeletal muscle
title_sort integrative analysis of gene expression, dna methylation, physiological traits, and genetic variation in human skeletal muscle
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561151/
https://www.ncbi.nlm.nih.gov/pubmed/31076557
http://dx.doi.org/10.1073/pnas.1814263116
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