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Coexpression Network Analysis in Abdominal and Gluteal Adipose Tissue Reveals Regulatory Genetic Loci for Metabolic Syndrome and Related Phenotypes

Metabolic Syndrome (MetS) is highly prevalent and has considerable public health impact, but its underlying genetic factors remain elusive. To identify gene networks involved in MetS, we conducted whole-genome expression and genotype profiling on abdominal (ABD) and gluteal (GLU) adipose tissue, and...

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Autores principales: Min, Josine L., Nicholson, George, Halgrimsdottir, Ingileif, Almstrup, Kristian, Petri, Andreas, Barrett, Amy, Travers, Mary, Rayner, Nigel W., Mägi, Reedik, Pettersson, Fredrik H., Broxholme, John, Neville, Matt J., Wills, Quin F., Cheeseman, Jane, Allen, Maxine, Holmes, Chris C., Spector, Tim D., Fleckner, Jan, McCarthy, Mark I., Karpe, Fredrik, Lindgren, Cecilia M., Zondervan, Krina T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3285582/
https://www.ncbi.nlm.nih.gov/pubmed/22383892
http://dx.doi.org/10.1371/journal.pgen.1002505
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author Min, Josine L.
Nicholson, George
Halgrimsdottir, Ingileif
Almstrup, Kristian
Petri, Andreas
Barrett, Amy
Travers, Mary
Rayner, Nigel W.
Mägi, Reedik
Pettersson, Fredrik H.
Broxholme, John
Neville, Matt J.
Wills, Quin F.
Cheeseman, Jane
Allen, Maxine
Holmes, Chris C.
Spector, Tim D.
Fleckner, Jan
McCarthy, Mark I.
Karpe, Fredrik
Lindgren, Cecilia M.
Zondervan, Krina T.
author_facet Min, Josine L.
Nicholson, George
Halgrimsdottir, Ingileif
Almstrup, Kristian
Petri, Andreas
Barrett, Amy
Travers, Mary
Rayner, Nigel W.
Mägi, Reedik
Pettersson, Fredrik H.
Broxholme, John
Neville, Matt J.
Wills, Quin F.
Cheeseman, Jane
Allen, Maxine
Holmes, Chris C.
Spector, Tim D.
Fleckner, Jan
McCarthy, Mark I.
Karpe, Fredrik
Lindgren, Cecilia M.
Zondervan, Krina T.
author_sort Min, Josine L.
collection PubMed
description Metabolic Syndrome (MetS) is highly prevalent and has considerable public health impact, but its underlying genetic factors remain elusive. To identify gene networks involved in MetS, we conducted whole-genome expression and genotype profiling on abdominal (ABD) and gluteal (GLU) adipose tissue, and whole blood (WB), from 29 MetS cases and 44 controls. Co-expression network analysis for each tissue independently identified nine, six, and zero MetS–associated modules of coexpressed genes in ABD, GLU, and WB, respectively. Of 8,992 probesets expressed in ABD or GLU, 685 (7.6%) were expressed in ABD and 51 (0.6%) in GLU only. Differential eigengene network analysis of 8,256 shared probesets detected 22 shared modules with high preservation across adipose depots (D(ABD-GLU) = 0.89), seven of which were associated with MetS (FDR P<0.01). The strongest associated module, significantly enriched for immune response–related processes, contained 94/620 (15%) genes with inter-depot differences. In an independent cohort of 145/141 twins with ABD and WB longitudinal expression data, median variability in ABD due to familiality was greater for MetS–associated versus un-associated modules (ABD: 0.48 versus 0.18, P = 0.08; GLU: 0.54 versus 0.20, P = 7.8×10(−4)). Cis-eQTL analysis of probesets associated with MetS (FDR P<0.01) and/or inter-depot differences (FDR P<0.01) provided evidence for 32 eQTLs. Corresponding eSNPs were tested for association with MetS–related phenotypes in two GWAS of >100,000 individuals; rs10282458, affecting expression of RARRES2 (encoding chemerin), was associated with body mass index (BMI) (P = 6.0×10(−4)); and rs2395185, affecting inter-depot differences of HLA-DRB1 expression, was associated with high-density lipoprotein (P = 8.7×10(−4)) and BMI–adjusted waist-to-hip ratio (P = 2.4×10(−4)). Since many genes and their interactions influence complex traits such as MetS, integrated analysis of genotypes and coexpression networks across multiple tissues relevant to clinical traits is an efficient strategy to identify novel associations.
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spelling pubmed-32855822012-03-01 Coexpression Network Analysis in Abdominal and Gluteal Adipose Tissue Reveals Regulatory Genetic Loci for Metabolic Syndrome and Related Phenotypes Min, Josine L. Nicholson, George Halgrimsdottir, Ingileif Almstrup, Kristian Petri, Andreas Barrett, Amy Travers, Mary Rayner, Nigel W. Mägi, Reedik Pettersson, Fredrik H. Broxholme, John Neville, Matt J. Wills, Quin F. Cheeseman, Jane Allen, Maxine Holmes, Chris C. Spector, Tim D. Fleckner, Jan McCarthy, Mark I. Karpe, Fredrik Lindgren, Cecilia M. Zondervan, Krina T. PLoS Genet Research Article Metabolic Syndrome (MetS) is highly prevalent and has considerable public health impact, but its underlying genetic factors remain elusive. To identify gene networks involved in MetS, we conducted whole-genome expression and genotype profiling on abdominal (ABD) and gluteal (GLU) adipose tissue, and whole blood (WB), from 29 MetS cases and 44 controls. Co-expression network analysis for each tissue independently identified nine, six, and zero MetS–associated modules of coexpressed genes in ABD, GLU, and WB, respectively. Of 8,992 probesets expressed in ABD or GLU, 685 (7.6%) were expressed in ABD and 51 (0.6%) in GLU only. Differential eigengene network analysis of 8,256 shared probesets detected 22 shared modules with high preservation across adipose depots (D(ABD-GLU) = 0.89), seven of which were associated with MetS (FDR P<0.01). The strongest associated module, significantly enriched for immune response–related processes, contained 94/620 (15%) genes with inter-depot differences. In an independent cohort of 145/141 twins with ABD and WB longitudinal expression data, median variability in ABD due to familiality was greater for MetS–associated versus un-associated modules (ABD: 0.48 versus 0.18, P = 0.08; GLU: 0.54 versus 0.20, P = 7.8×10(−4)). Cis-eQTL analysis of probesets associated with MetS (FDR P<0.01) and/or inter-depot differences (FDR P<0.01) provided evidence for 32 eQTLs. Corresponding eSNPs were tested for association with MetS–related phenotypes in two GWAS of >100,000 individuals; rs10282458, affecting expression of RARRES2 (encoding chemerin), was associated with body mass index (BMI) (P = 6.0×10(−4)); and rs2395185, affecting inter-depot differences of HLA-DRB1 expression, was associated with high-density lipoprotein (P = 8.7×10(−4)) and BMI–adjusted waist-to-hip ratio (P = 2.4×10(−4)). Since many genes and their interactions influence complex traits such as MetS, integrated analysis of genotypes and coexpression networks across multiple tissues relevant to clinical traits is an efficient strategy to identify novel associations. Public Library of Science 2012-02-23 /pmc/articles/PMC3285582/ /pubmed/22383892 http://dx.doi.org/10.1371/journal.pgen.1002505 Text en Min et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Min, Josine L.
Nicholson, George
Halgrimsdottir, Ingileif
Almstrup, Kristian
Petri, Andreas
Barrett, Amy
Travers, Mary
Rayner, Nigel W.
Mägi, Reedik
Pettersson, Fredrik H.
Broxholme, John
Neville, Matt J.
Wills, Quin F.
Cheeseman, Jane
Allen, Maxine
Holmes, Chris C.
Spector, Tim D.
Fleckner, Jan
McCarthy, Mark I.
Karpe, Fredrik
Lindgren, Cecilia M.
Zondervan, Krina T.
Coexpression Network Analysis in Abdominal and Gluteal Adipose Tissue Reveals Regulatory Genetic Loci for Metabolic Syndrome and Related Phenotypes
title Coexpression Network Analysis in Abdominal and Gluteal Adipose Tissue Reveals Regulatory Genetic Loci for Metabolic Syndrome and Related Phenotypes
title_full Coexpression Network Analysis in Abdominal and Gluteal Adipose Tissue Reveals Regulatory Genetic Loci for Metabolic Syndrome and Related Phenotypes
title_fullStr Coexpression Network Analysis in Abdominal and Gluteal Adipose Tissue Reveals Regulatory Genetic Loci for Metabolic Syndrome and Related Phenotypes
title_full_unstemmed Coexpression Network Analysis in Abdominal and Gluteal Adipose Tissue Reveals Regulatory Genetic Loci for Metabolic Syndrome and Related Phenotypes
title_short Coexpression Network Analysis in Abdominal and Gluteal Adipose Tissue Reveals Regulatory Genetic Loci for Metabolic Syndrome and Related Phenotypes
title_sort coexpression network analysis in abdominal and gluteal adipose tissue reveals regulatory genetic loci for metabolic syndrome and related phenotypes
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3285582/
https://www.ncbi.nlm.nih.gov/pubmed/22383892
http://dx.doi.org/10.1371/journal.pgen.1002505
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