title: Extent, causes, and consequences of small RNA expression variation in human adipose tissue.
abstract: Small RNAs are functional molecules that modulate mRNA transcripts and have been implicated in the aetiology of several common diseases. However, little is known about the extent of their variability within the human population. Here, we characterise the extent, causes, and effects of naturally occurring variation in expression and sequence of small RNAs from adipose tissue in relation to genotype, gene expression, and metabolic traits in the MuTHER reference cohort. We profiled the expression of 15 to 30 base pair RNA molecules in subcutaneous adipose tissue from 131 individuals using high-throughput sequencing, and quantified levels of 591 microRNAs and small nucleolar RNAs. We identified three genetic variants and three RNA editing events. Highly expressed small RNAs are more conserved within mammals than average, as are those with highly variable expression. We identified 14 genetic loci significantly associated with nearby small RNA expression levels, seven of which also regulate an mRNA transcript level in the same region. In addition, these loci are enriched for variants significant in genome-wide association studies for body mass index. Contrary to expectation, we found no evidence for negative correlation between expression level of a microRNA and its target mRNAs. Trunk fat mass, body mass index, and fasting insulin were associated with more than twenty small RNA expression levels each, while fasting glucose had no significant associations. This study highlights the similar genetic complexity and shared genetic control of small RNA and mRNA transcripts, and gives a quantitative picture of small RNA expression variation in the human population.
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Leopold
authors.initials: L
authors.lastname: Parts
authors.forename: Åsa K
authors.initials: ÅK
authors.lastname: Hedman
authors.forename: Sarah
authors.initials: S
authors.lastname: Keildson
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Knights
authors.forename: Cei
authors.initials: C
authors.lastname: Abreu-Goodger
authors.forename: Martijn
authors.initials: M
authors.lastname: van de Bunt
authors.forename: José Afonso
authors.initials: JA
authors.lastname: Guerra-Assunção
authors.forename: Nenad
authors.initials: N
authors.lastname: Bartonicek
authors.forename: Stijn
authors.initials: S
authors.lastname: van Dongen
authors.forename: Reedik
authors.initials: R
authors.lastname: Mägi
authors.forename: James
authors.initials: J
authors.lastname: Nisbet
authors.forename: Amy
authors.initials: A
authors.lastname: Barrett
authors.forename: Mattias
authors.initials: M
authors.lastname: Rantalainen
authors.forename: Alexandra C
authors.initials: AC
authors.lastname: Nica
authors.forename: Michael A
authors.initials: MA
authors.lastname: Quail
authors.forename: Kerrin S
authors.initials: KS
authors.lastname: Small
authors.forename: Daniel
authors.initials: D
authors.lastname: Glass
authors.forename: Anton J
authors.initials: AJ
authors.lastname: Enright
authors.forename: John
authors.initials: J
authors.lastname: Winn
authors.forename: Panos
authors.initials: P
authors.lastname: Deloukas
authors.forename: Emmanouil T
authors.initials: ET
authors.lastname: Dermitzakis
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Spector
authors.forename: Richard
authors.initials: R
authors.lastname: Durbin
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: Lindgren
mesh_terms: D000818:Animals; D001786:Blood Glucose; D050218:Body Fat Distribution; D015992:Body Mass Index; D005215:Fasting; D005260:Female; D005786:Gene Expression Regulation; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007328:Insulin / Q000097:blood; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D020537:RNA, Small Nucleolar / Q000235:genetics / Q000378:metabolism; D058727:RNA, Small Untranslated / Q000235:genetics* / Q000378:metabolism; D050151:Subcutaneous Fat / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D007328:Insulin; D035683:MicroRNAs; D012333:RNA, Messenger; D020537:RNA, Small Nucleolar; D058727:RNA, Small Untranslated