title: The Genetic Architecture of Gene Expression in Peripheral Blood.
abstract: We analyzed the mRNA levels for 36,778 transcript expression traits (probes) from 2,765 individuals to comprehensively investigate the genetic architecture and degree of missing heritability for gene expression in peripheral blood. We identified 11,204 cis and 3,791 trans independent expression quantitative trait loci (eQTL) by using linear mixed models to perform genome-wide association analyses. Furthermore, using information on both closely and distantly related individuals, heritability was estimated for all expression traits. Of the set of expressed probes (15,966), 10,580 (66%) had an estimated narrow-sense heritability (h2) greater than zero with a mean (median) value of 0.192 (0.142). Across these probes, on average the proportion of genetic variance explained by all eQTL (hCOJO2) was 31% (0.060/0.192), meaning that 69% is missing, with the sentinel SNP of the largest eQTL explaining 87% (0.052/0.060) of the variance attributed to all identified cis- and trans-eQTL. For the same set of probes, the genetic variance attributed to genome-wide common (MAF > 0.01) HapMap 3 SNPs (hg2) accounted for on average 48% (0.093/0.192) of h2. Taken together, the evidence suggests that approximately half the genetic variance for gene expression is not tagged by common SNPs, and of the variance that is tagged by common SNPs, a large proportion can be attributed to identifiable eQTL of large effect, typically in cis. Finally, we present evidence that, compared with a meta-analysis, using individual-level data results in an increase of approximately 50% in power to detect eQTL.
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia; Queensland Brain Institute, University of Queensland, Brisbane, QLD 4072, Australia. Electronic address: l.lloydjones@uq.edu.au.
authors.forename: Luke R
authors.initials: LR
authors.lastname: Lloyd-Jones
authors.affiliation: Queensland Brain Institute, University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Alexander
authors.initials: A
authors.lastname: Holloway
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Allan
authors.initials: A
authors.lastname: McRae
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia; Queensland Brain Institute, University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 7EH, UK.
authors.forename: Kerrin
authors.initials: K
authors.lastname: Small
authors.affiliation: School of Biology and Center for Integrative Genomics, Georgia Institute of Technology, Atlanta, GA 30332, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: School of Biology and Center for Integrative Genomics, Georgia Institute of Technology, Atlanta, GA 30332, USA.
authors.forename: Biao
authors.initials: B
authors.lastname: Zeng
authors.affiliation: Queensland Brain Institute, University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Bakshi
authors.affiliation: Estonian Genome Center, University of Tartu, Tartu 51010, Estonia.
authors.forename: Andres
authors.initials: A
authors.lastname: Metspalu
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva, Geneva 1211, Switzerland.
authors.forename: Manolis
authors.initials: M
authors.lastname: Dermitzakis
authors.affiliation: School of Biology and Center for Integrative Genomics, Georgia Institute of Technology, Atlanta, GA 30332, USA.
authors.forename: Greg
authors.initials: G
authors.lastname: Gibson
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 7EH, UK.
authors.forename: Tim
authors.initials: T
authors.lastname: Spector
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Grant
authors.initials: G
authors.lastname: Montgomery
authors.affiliation: Estonian Genome Center, University of Tartu, Tartu 51010, Estonia.
authors.forename: Tonu
authors.initials: T
authors.lastname: Esko
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia; Queensland Brain Institute, University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Visscher
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia; Queensland Brain Institute, University of Queensland, Brisbane, QLD 4072, Australia. Electronic address: joseph.powell@uq.edu.au.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Powell
mesh_terms: D015870:Gene Expression; D056726:Genetic Association Studies; D015894:Genome, Human; D005838:Genotype; D060148:HapMap Project; D006801:Humans; D040582:Inheritance Patterns; D016014:Linear Models; D015810:Linkage Disequilibrium; D008957:Models, Genetic; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012333:RNA, Messenger / Q000097:blood* / Q000235:genetics
chemical_list: D012333:RNA, Messenger
keywords: gene expression; genetic architecture; genetic association study; heritability; linear mixed models