title: Cis and trans effects of human genomic variants on gene expression.
abstract: Gene expression is a heritable cellular phenotype that defines the function of a cell and can lead to diseases in case of misregulation. In order to detect genetic variations affecting gene expression, we performed association analysis of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) with gene expression measured in 869 lymphoblastoid cell lines of the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort in cis and in trans. We discovered that 3,534 genes (false discovery rate (FDR) = 5%) are affected by an expression quantitative trait locus (eQTL) in cis and 48 genes are affected in trans. We observed that CNVs are more likely to be eQTLs than SNPs. In addition, we found that variants associated to complex traits and diseases are enriched for trans-eQTLs and that trans-eQTLs are enriched for cis-eQTLs. As a variant affecting both a gene in cis and in trans suggests that the cis gene is functionally linked to the trans gene expression, we looked specifically for trans effects of cis-eQTLs. We discovered that 26 cis-eQTLs are associated to 92 genes in trans with the cis-eQTLs of the transcriptions factors BATF3 and HMX2 affecting the most genes. We then explored if the variation of the level of expression of the cis genes were causally affecting the level of expression of the trans genes and discovered several causal relationships between variation in the level of expression of the cis gene and variation of the level of expression of the trans gene. This analysis shows that a large sample size allows the discovery of secondary effects of human variations on gene expression that can be used to construct short directed gene regulatory networks.
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland; Institute of Genetics and Genomics in Geneva (iGE3), Geneva, Switzerland; Swiss Institute of Bioinformatics (SIB), Geneva, Switzerland.
authors.forename: Julien
authors.initials: J
authors.lastname: Bryois
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland; Institute of Genetics and Genomics in Geneva (iGE3), Geneva, Switzerland; Swiss Institute of Bioinformatics (SIB), Geneva, Switzerland.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Buil
authors.affiliation: MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom; School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom; University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: David M
authors.initials: DM
authors.lastname: Evans
authors.affiliation: MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom; School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: John P
authors.initials: JP
authors.lastname: Kemp
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland; Department of Pathology and Genetics, Stanford University, Stanford, California, United States of America.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Montgomery
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Donald F
authors.initials: DF
authors.lastname: Conrad
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Karen M
authors.initials: KM
authors.lastname: Ho
authors.affiliation: MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom; School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Susan
authors.initials: S
authors.lastname: Ring
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Matthew
authors.initials: M
authors.lastname: Hurles
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, United Kingdom; William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kindom; Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia.
authors.forename: Panos
authors.initials: P
authors.lastname: Deloukas
authors.affiliation: MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom; School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: George
authors.initials: G
authors.lastname: Davey Smith
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland; Institute of Genetics and Genomics in Geneva (iGE3), Geneva, Switzerland; Swiss Institute of Bioinformatics (SIB), Geneva, Switzerland; Center of Excellence for Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia.
authors.forename: Emmanouil T
authors.initials: ET
authors.lastname: Dermitzakis
mesh_terms: D045744:Cell Line, Tumor; D056915:DNA Copy Number Variations / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics*; D053263:Gene Regulatory Networks; D056726:Genetic Association Studies; D015894:Genome, Human; D023281:Genomics; D006801:Humans; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics*