TY - JOUR
T1 - Characterizing the Relation Between Expression QTLs and Complex Traits
T2 - Exploring the Role of Tissue Specificity
AU - UK Brain Expression Consortium
AU - Ip, Hill F.
AU - Jansen, Rick
AU - Abdellaoui, Abdel
AU - Bartels, Meike
AU - Ryten, Mina
AU - Hardy, John
AU - Weale, Michael E.
AU - Ramasamy, Adaikalavan
AU - Forabosco, Paola
AU - Matarin, Mar
AU - Vandrovcova, Jana
AU - Botia, Juan A.
AU - D’Sa, Karishma
AU - Guelfi, Sebastian
AU - Smith, Colin
AU - Walker, Robert
AU - Reynolds, Regina H.
AU - Zhang, David
AU - Trabzuni, Daniah
AU - Boomsma, Dorret I.
AU - Nivard, Michel G.
AU - Consortium, UK Brain Expression
N1 - Funding Information: Funding MGN is supported by the Royal Netherlands Academy of Science Professor Award (PAH/6635) to DIB. HFI is supported by the “Aggression in Children: Unraveling gene-environment interplay to inform Treatment and InterventiON strategies” (ACTION) project. ACTION receives funding from the European Union Seventh Frame-work Program (FP7/2007–2013) under grant agreement no 602768. MB is supported by a University Research Chair of the Vrije Univer-siteit. The discovery of blood eQTL was funded by the US National Institute of Mental Health (RC2 MH089951, principal Investigator PFS) as part of the American Recovery and Reinvestment Act of 2009. We acknowledge Hillary Finucane, Raymond Walters and Benjamin Neale for critical comments on our methods, design and manuscript. Funding Information: Members of the UBKEC consortium: Mina Ryten (University College London, UK), John Hardy (University College London, UK), Michael E. Weale (King?s College London, UK), Adaikalavan Ramasamy (King?s College London, UK), Paola Forabosco (Cittadella Universitaria di Monserrato, Italy), Mar Matarin (University College London, UK), Jana Vandrovcova (University College London, UK), Juan A. Botia (Universidad de Murcia, Spain), Karishma D?Sa (University College London, UK), Sebastian Guelfi (University College London, UK), Colin Smith (University of Edinburgh, UK), Robert Walker (University of Edinburgh, UK), Regina H. Reynolds (University College London, UK), David Zhang (University College London, UK), Daniah Trabzuni (University College London, UK). Edited by Sarah Medland. Authors of UKBEC are listed in the acknowledgement. Hill F. Ip, Rick Jansen, Abdel Abdellaoui, Meike Bartels, Dorret I. Boomsma, and Michel G. Nivard?declare that they have no conflict of interest. Publisher Copyright: © 2018, The Author(s).
PY - 2018/9/1
Y1 - 2018/9/1
N2 - Measurement of gene expression levels and detection of eQTLs (expression quantitative trait loci) are difficult in tissues with limited sample availability, such as the brain. However, eQTL overlap between tissues might be high, which would allow for inference of eQTL functioning in the brain via eQTLs detected in readily accessible tissues, e.g. whole blood. Applying Stratified Linkage Disequilibrium Score Regression (SLDSR), we quantified the enrichment in polygenic signal of blood and brain eQTLs in genome-wide association studies (GWAS) of 11 complex traits. We looked at eQTLs discovered in 44 tissues by the Genotype-Tissue Expression (GTEx) consortium and two other large representative studies, and found no tissue-specific eQTL effects. Next, we integrated the GTEx eQTLs with regions associated with tissue-specific histone modifiers, and interrogated their effect on rheumatoid arthritis and schizophrenia. We observed substantially enriched effects of eQTLs located inside regions bearing modification H3K4me1 on schizophrenia, but not rheumatoid arthritis, and not tissue-specific. Finally, we extracted eQTLs associated with tissue-specific differentially expressed genes and determined their effects on rheumatoid arthritis and schizophrenia, these analysis revealed limited enrichment of eQTLs associated with gene specifically expressed in specific tissues. Our results pointed to strong enrichment of eQTLs in their effect on complex traits, without evidence for tissue-specific effects. Lack of tissue-specificity can be either due to a lack of statistical power or due to the true absence of tissue-specific effects. We conclude that eQTLs are strongly enriched in GWAS signal and that the enrichment is not specific to the eQTL discovery tissue. Until sample sizes for eQTL discovery grow sufficiently large, working with relatively accessible tissues as proxy for eQTL discovery is sensible and restricting lookups for GWAS hits to a specific tissue for which limited samples are available might not be advisable.
AB - Measurement of gene expression levels and detection of eQTLs (expression quantitative trait loci) are difficult in tissues with limited sample availability, such as the brain. However, eQTL overlap between tissues might be high, which would allow for inference of eQTL functioning in the brain via eQTLs detected in readily accessible tissues, e.g. whole blood. Applying Stratified Linkage Disequilibrium Score Regression (SLDSR), we quantified the enrichment in polygenic signal of blood and brain eQTLs in genome-wide association studies (GWAS) of 11 complex traits. We looked at eQTLs discovered in 44 tissues by the Genotype-Tissue Expression (GTEx) consortium and two other large representative studies, and found no tissue-specific eQTL effects. Next, we integrated the GTEx eQTLs with regions associated with tissue-specific histone modifiers, and interrogated their effect on rheumatoid arthritis and schizophrenia. We observed substantially enriched effects of eQTLs located inside regions bearing modification H3K4me1 on schizophrenia, but not rheumatoid arthritis, and not tissue-specific. Finally, we extracted eQTLs associated with tissue-specific differentially expressed genes and determined their effects on rheumatoid arthritis and schizophrenia, these analysis revealed limited enrichment of eQTLs associated with gene specifically expressed in specific tissues. Our results pointed to strong enrichment of eQTLs in their effect on complex traits, without evidence for tissue-specific effects. Lack of tissue-specificity can be either due to a lack of statistical power or due to the true absence of tissue-specific effects. We conclude that eQTLs are strongly enriched in GWAS signal and that the enrichment is not specific to the eQTL discovery tissue. Until sample sizes for eQTL discovery grow sufficiently large, working with relatively accessible tissues as proxy for eQTL discovery is sensible and restricting lookups for GWAS hits to a specific tissue for which limited samples are available might not be advisable.
KW - Brain
KW - Complex human traits
KW - Enrichment
KW - Gene expression
KW - Genome-wide
KW - SLDSR
KW - Stratified linkage disequilibrium score regression
KW - Tissue-specificity
KW - Whole blood
KW - eQTL discovery
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U2 - https://doi.org/10.1007/s10519-018-9914-2
DO - https://doi.org/10.1007/s10519-018-9914-2
M3 - Article
C2 - 30030655
SN - 0001-8244
VL - 48
SP - 374
EP - 385
JO - Behavior genetics
JF - Behavior genetics
IS - 5
ER -