title: The use of genome-wide eQTL associations in lymphoblastoid cell lines to identify novel genetic pathways involved in complex traits.
abstract: The integrated analysis of genotypic and expression data for association with complex traits could identify novel genetic pathways involved in complex traits. We profiled 19,573 expression probes in Epstein-Barr virus-transformed lymphoblastoid cell lines (LCLs) from 299 twins and correlated these with 44 quantitative traits (QTs). For 939 expressed probes correlating with more than one QT, we investigated the presence of eQTL associations in three datasets of 57 CEU HapMap founders and 86 unrelated twins. Genome-wide association analysis of these probes with 2.2 m SNPs revealed 131 potential eQTLs (1,989 eQTL SNPs) overlapping between the HapMap datasets, five of which were in cis (58 eQTL SNPs). We then tested 535 SNPs tagging the eQTL SNPs, for association with the relevant QT in 2,905 twins. We identified nine potential SNP-QT associations (P<0.01) but none significantly replicated in five large consortia of 1,097-16,129 subjects. We also failed to replicate previous reported eQTL associations with body mass index, plasma low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides levels derived from lymphocytes, adipose and liver tissue. Our results and additional power calculations suggest that proponents may have been overoptimistic in the power of LCLs in eQTL approaches to elucidate regulatory genetic effects on complex traits using the small datasets generated to date. Nevertheless, larger tissue-specific expression data sets relevant to specific traits are becoming available, and should enable the adoption of similar integrated analyses in the near future.
authors.affiliation: Genetic and Genomic Epidemiology Unit, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom. josine.min@well.ox.ac.uk
authors.forename: Josine L
authors.initials: JL
authors.lastname: Min
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Taylor
authors.forename: J Brent
authors.initials: JB
authors.lastname: Richards
authors.forename: Tim
authors.initials: T
authors.lastname: Watts
authors.forename: Fredrik H
authors.initials: FH
authors.lastname: Pettersson
authors.forename: John
authors.initials: J
authors.lastname: Broxholme
authors.forename: Kourosh R
authors.initials: KR
authors.lastname: Ahmadi
authors.forename: Gabriela L
authors.initials: GL
authors.lastname: Surdulescu
authors.forename: Ernesto
authors.initials: E
authors.lastname: Lowy
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.forename: Chris
authors.initials: C
authors.lastname: Newton-Cheh
authors.forename: Markus
authors.initials: M
authors.lastname: Perola
authors.forename: Nicole
authors.initials: N
authors.lastname: Soranzo
authors.forename: Ida
authors.initials: I
authors.lastname: Surakka
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: Lindgren
authors.forename: Jiannis
authors.initials: J
authors.lastname: Ragoussis
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Morris
authors.forename: Lon R
authors.initials: LR
authors.lastname: Cardon
authors.forename: Tim D
authors.initials: TD
authors.lastname: Spector
authors.forename: Krina T
authors.initials: KT
authors.lastname: Zondervan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002460:Cell Line; D015331:Cohort Studies; D030541:Databases, Genetic; D005260:Female; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics*; D055106:Genome-Wide Association Study; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D040582:Inheritance Patterns / Q000235:genetics; D008214:Lymphocytes / Q000378:metabolism*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D025341:Principal Component Analysis; D040641:Quantitative Trait Loci / Q000235:genetics*; D019655:Quantitative Trait, Heritable; D015203:Reproducibility of Results; D018401:Sample Size; D055815:Young Adult