title: Functional characterisation of ADIPOQ variants using individuals recruited by genotype.
abstract: Four non-coding GWAS variants in or near the ADIPOQ gene (rs17300539, rs17366653, rs3821799 and rs56354395) together explain 4% of the variation in circulating adiponectin. The functional basis for this is unknown. We tested the effect of these variants on ADIPOQ transcription, splicing and stability respectively in adipose tissue samples from participants recruited by rs17366653 genotype. Transcripts carrying rs17300539 demonstrated a 17% increase in expression (p = 0.001). Variant rs17366653 was associated with disruption of ADIPOQ splicing leading to a 7 fold increase in levels of a non-functional transcript (p = 0.002). Transcripts carrying rs56354395 demonstrated a 59% decrease in expression (p = <0.0001). No effects of rs3821799 genotype on expression was observed. Association between variation in the ADIPOQ gene and serum adiponectin may arise from effects on mRNA transcription, splicing or stability. These studies illustrate the utility of recruit-by-genotype studies in relevant human tissues in functional interpretation of GWAS signals.
authors.affiliation: Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter, Devon, EX2 5DW, UK.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Lee
authors.affiliation: Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter, Devon, EX2 5DW, UK.
authors.forename: Henry O
authors.initials: HO
authors.lastname: Lloyd-Laney
authors.affiliation: Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter, Devon, EX2 5DW, UK.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Locke
authors.affiliation: Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter, Devon, EX2 5DW, UK.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: McCulloch
authors.affiliation: Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter, Devon, EX2 5DW, UK.
authors.forename: Bridget
authors.initials: B
authors.lastname: Knight
authors.affiliation: Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter, Devon, EX2 5DW, UK.
authors.forename: Hanieh
authors.initials: H
authors.lastname: Yaghootkar
authors.affiliation: Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter, Devon, EX2 5DW, UK.
authors.forename: Giles
authors.initials: G
authors.lastname: Cory
authors.affiliation: Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter, Devon, EX2 5DW, UK.
authors.forename: Katarina
authors.initials: K
authors.lastname: Kos
authors.affiliation: Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter, Devon, EX2 5DW, UK.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Frayling
authors.affiliation: Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter, Devon, EX2 5DW, UK. Electronic address: L.W.Harries@exeter.ac.uk.
authors.forename: Lorna W
authors.initials: LW
authors.lastname: Harries
mesh_terms: D052242:Adiponectin / Q000097:blood / Q000235:genetics*; D000273:Adipose Tissue / Q000378:metabolism; D000483:Alleles; D001483:Base Sequence; D019295:Computational Biology; D005260:Female; D005786:Gene Expression Regulation; D005787:Gene Frequency / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012322:RNA Precursors / Q000235:genetics; D012326:RNA Splicing / Q000235:genetics; D062085:RNA, Long Noncoding / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: C499918:ADIPOQ protein, human; D052242:Adiponectin; D012322:RNA Precursors; D062085:RNA, Long Noncoding; D012333:RNA, Messenger
keywords: ADIPOQ; Adiponectin; Functional studies; Genetic variation; mRNA