title: Dissecting the genetics of the human transcriptome identifies novel trait-related trans-eQTLs and corroborates the regulatory relevance of non-protein coding loci†.
abstract: Genetics of gene expression (eQTLs or expression QTLs) has proved an indispensable tool for understanding biological pathways and pathomechanisms of trait-associated SNPs. However, power of most genome-wide eQTL studies is still limited. We performed a large eQTL study in peripheral blood mononuclear cells of 2112 individuals increasing the power to detect trans-effects genome-wide. Going beyond univariate SNP-transcript associations, we analyse relations of eQTLs to biological pathways, polygenetic effects of expression regulation, trans-clusters and enrichment of co-localized functional elements. We found eQTLs for about 85% of analysed genes, and 18% of genes were trans-regulated. Local eSNPs were enriched up to a distance of 5 Mb to the transcript challenging typically implemented ranges of cis-regulations. Pathway enrichment within regulated genes of GWAS-related eSNPs supported functional relevance of identified eQTLs. We demonstrate that nearest genes of GWAS-SNPs might frequently be misleading functional candidates. We identified novel trans-clusters of potential functional relevance for GWAS-SNPs of several phenotypes including obesity-related traits, HDL-cholesterol levels and haematological phenotypes. We used chromatin immunoprecipitation data for demonstrating biological effects. Yet, we show for strongly heritable transcripts that still little trans-chromosomal heritability is explained by all identified trans-eSNPs; however, our data suggest that most cis-heritability of these transcripts seems explained. Dissection of co-localized functional elements indicated a prominent role of SNPs in loci of pseudogenes and non-coding RNAs for the regulation of coding genes. In summary, our study substantially increases the catalogue of human eQTLs and improves our understanding of the complex genetic regulation of gene expression, pathways and disease-related processes.
authors.affiliation: Institute for Medical Informatics, Statistics and Epidemiology, LIFE - Leipzig Research Center for Civilization Diseases, Cognitive Genetics, Department of Cell Therapy.
authors.forename: Holger
authors.initials: H
authors.lastname: Kirsten
authors.affiliation: Department for Computer Science, Analysis Strategies Group, Department of Diagnostics, Young Investigators Group Bioinformatics and Transcriptomics, Department Proteomics, Helmholtz Centre for Environmental Research - UFZ, Leipzig, Germany and.
authors.forename: Hoor
authors.initials: H
authors.lastname: Al-Hasani
authors.affiliation: Institute of Laboratory Medicine, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Lesca
authors.initials: L
authors.lastname: Holdt
authors.affiliation: Institute for Medical Informatics, Statistics and Epidemiology, LIFE - Leipzig Research Center for Civilization Diseases.
authors.forename: Arnd
authors.initials: A
authors.lastname: Gross
authors.affiliation: LIFE - Leipzig Research Center for Civilization Diseases, Department of Internal Medicine/Cardiology, Heart Center.
authors.forename: Frank
authors.initials: F
authors.lastname: Beutner
authors.affiliation: Interdisciplinary Center for Clinical Research, Faculty of Medicine and .
authors.forename: Knut
authors.initials: K
authors.lastname: Krohn
authors.affiliation: Institute for Medical Informatics, Statistics and Epidemiology, LIFE - Leipzig Research Center for Civilization Diseases.
authors.forename: Katrin
authors.initials: K
authors.lastname: Horn
authors.affiliation: Institute for Medical Informatics, Statistics and Epidemiology, LIFE - Leipzig Research Center for Civilization Diseases.
authors.forename: Peter
authors.initials: P
authors.lastname: Ahnert
authors.affiliation: LIFE - Leipzig Research Center for Civilization Diseases, Institute of Laboratory Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Ralph
authors.initials: R
authors.lastname: Burkhardt
authors.affiliation: Department for Computer Science, RNomics Group, Department of Diagnostics, Fraunhofer Institute for Cell Therapy and Immunology- IZI, Leipzig, Germany, Young Investigators Group Bioinformatics and Transcriptomics, Department Proteomics, Helmholtz Centre for Environmental Research - UFZ, Leipzig, Germany and.
authors.forename: Kristin
authors.initials: K
authors.lastname: Reiche
authors.affiliation: Department for Computer Science, RNomics Group, Department of Diagnostics, Fraunhofer Institute for Cell Therapy and Immunology- IZI, Leipzig, Germany, Young Investigators Group Bioinformatics and Transcriptomics, Department Proteomics, Helmholtz Centre for Environmental Research - UFZ, Leipzig, Germany and.
authors.forename: Jörg
authors.initials: J
authors.lastname: Hackermüller
authors.affiliation: Institute for Medical Informatics, Statistics and Epidemiology, LIFE - Leipzig Research Center for Civilization Diseases.
authors.forename: Markus
authors.initials: M
authors.lastname: Löffler
authors.affiliation: Institute of Laboratory Medicine, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Teupser
authors.affiliation: LIFE - Leipzig Research Center for Civilization Diseases, Institute of Laboratory Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Thiery
authors.affiliation: Institute for Medical Informatics, Statistics and Epidemiology, LIFE - Leipzig Research Center for Civilization Diseases, markus.scholz@imise.uni-leipzig.de.
authors.forename: Markus
authors.initials: M
authors.lastname: Scholz
mesh_terms: D005260:Female; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D006801:Humans; D007963:Leukocytes, Mononuclear; D008297:Male; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012045:Regulatory Sequences, Nucleic Acid