title: Coexpression network analysis in abdominal and gluteal adipose tissue reveals regulatory genetic loci for metabolic syndrome and related phenotypes.
abstract: 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.
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom. jlmin@well.ox.ac.uk
authors.forename: Josine L
authors.initials: JL
authors.lastname: Min
authors.forename: George
authors.initials: G
authors.lastname: Nicholson
authors.forename: Ingileif
authors.initials: I
authors.lastname: Halgrimsdottir
authors.forename: Kristian
authors.initials: K
authors.lastname: Almstrup
authors.forename: Andreas
authors.initials: A
authors.lastname: Petri
authors.forename: Amy
authors.initials: A
authors.lastname: Barrett
authors.forename: Mary
authors.initials: M
authors.lastname: Travers
authors.forename: Nigel W
authors.initials: NW
authors.lastname: Rayner
authors.forename: Reedik
authors.initials: R
authors.lastname: Mägi
authors.forename: Fredrik H
authors.initials: FH
authors.lastname: Pettersson
authors.forename: John
authors.initials: J
authors.lastname: Broxholme
authors.forename: Matt J
authors.initials: MJ
authors.lastname: Neville
authors.forename: Quin F
authors.initials: QF
authors.lastname: Wills
authors.forename: Jane
authors.initials: J
authors.lastname: Cheeseman
authors.forename: Maxine
authors.initials: M
authors.lastname: Allen
authors.forename: Chris C
authors.initials: CC
authors.lastname: Holmes
authors.forename: Tim D
authors.initials: TD
authors.lastname: Spector
authors.forename: Jan
authors.initials: J
authors.lastname: Fleckner
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.forename: Fredrik
authors.initials: F
authors.lastname: Karpe
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: Lindgren
authors.forename: Krina T
authors.initials: KT
authors.lastname: Zondervan
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D015992:Body Mass Index; D018925:Chemokines / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D059811:HLA-DRB1 Chains / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D024821:Metabolic Syndrome / Q000235:genetics* / Q000473:pathology; D009928:Organ Specificity; D010641:Phenotype; D040641:Quantitative Trait Loci
chemical_list: D018925:Chemokines; D059811:HLA-DRB1 Chains; D036341:Intercellular Signaling Peptides and Proteins; C478630:RARRES2 protein, human