title: Powerful identification of cis-regulatory SNPs in human primary monocytes using allele-specific gene expression.
abstract: A large number of genome-wide association studies have been performed during the past five years to identify associations between SNPs and human complex diseases and traits. The assignment of a functional role for the identified disease-associated SNP is not straight-forward. Genome-wide expression quantitative trait locus (eQTL) analysis is frequently used as the initial step to define a function while allele-specific gene expression (ASE) analysis has not yet gained a wide-spread use in disease mapping studies. We compared the power to identify cis-acting regulatory SNPs (cis-rSNPs) by genome-wide allele-specific gene expression (ASE) analysis with that of traditional expression quantitative trait locus (eQTL) mapping. Our study included 395 healthy blood donors for whom global gene expression profiles in circulating monocytes were determined by Illumina BeadArrays. ASE was assessed in a subset of these monocytes from 188 donors by quantitative genotyping of mRNA using a genome-wide panel of SNP markers. The performance of the two methods for detecting cis-rSNPs was evaluated by comparing associations between SNP genotypes and gene expression levels in sample sets of varying size. We found that up to 8-fold more samples are required for eQTL mapping to reach the same statistical power as that obtained by ASE analysis for the same rSNPs. The performance of ASE is insensitive to SNPs with low minor allele frequencies and detects a larger number of significantly associated rSNPs using the same sample size as eQTL mapping. An unequivocal conclusion from our comparison is that ASE analysis is more sensitive for detecting cis-rSNPs than standard eQTL mapping. Our study shows the potential of ASE mapping in tissue samples and primary cells which are difficult to obtain in large numbers.
authors.affiliation: Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Jonas Carlsson
authors.initials: JC
authors.lastname: Almlöf
authors.forename: Per
authors.initials: P
authors.lastname: Lundmark
authors.forename: Anders
authors.initials: A
authors.lastname: Lundmark
authors.forename: Bing
authors.initials: B
authors.lastname: Ge
authors.forename: Seraya
authors.initials: S
authors.lastname: Maouche
authors.forename: Harald H H
authors.initials: HH
authors.lastname: Göring
authors.forename: Ulrika
authors.initials: U
authors.lastname: Liljedahl
authors.forename: Camilla
authors.initials: C
authors.lastname: Enström
authors.forename: Jessy
authors.initials: J
authors.lastname: Brocheton
authors.forename: Carole
authors.initials: C
authors.lastname: Proust
authors.forename: Tiphaine
authors.initials: T
authors.lastname: Godefroy
authors.forename: Jennifer G
authors.initials: JG
authors.lastname: Sambrook
authors.forename: Jennifer
authors.initials: J
authors.lastname: Jolley
authors.forename: Abigail
authors.initials: A
authors.lastname: Crisp-Hihn
authors.forename: Nicola
authors.initials: N
authors.lastname: Foad
authors.forename: Heather
authors.initials: H
authors.lastname: Lloyd-Jones
authors.forename: Jonathan
authors.initials: J
authors.lastname: Stephens
authors.forename: Rhian
authors.initials: R
authors.lastname: Gwilliam
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Rice
authors.forename: Christian
authors.initials: C
authors.lastname: Hengstenberg
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
authors.forename: Jeanette
authors.initials: J
authors.lastname: Erdmann
authors.forename: Heribert
authors.initials: H
authors.lastname: Schunkert
authors.forename: Tomi
authors.initials: T
authors.lastname: Pastinen
authors.forename: Panos
authors.initials: P
authors.lastname: Deloukas
authors.forename: Alison H
authors.initials: AH
authors.lastname: Goodall
authors.forename: Willem H
authors.initials: WH
authors.lastname: Ouwehand
authors.forename: François
authors.initials: F
authors.lastname: Cambien
authors.forename: Ann-Christine
authors.initials: AC
authors.lastname: Syvänen
mesh_terms: D000483:Alleles; D002874:Chromosome Mapping; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics*; D005787:Gene Frequency / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D009000:Monocytes / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D040641:Quantitative Trait Loci / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*
chemical_list: D005819:Genetic Markers; D012333:RNA, Messenger