Cell Specific eQTL Analysis without Sorting Cells

PLoS Genet. 2015 May 8;11(5):e1005223. doi: 10.1371/journal.pgen.1005223. eCollection 2015 May.

Abstract

The functional consequences of trait associated SNPs are often investigated using expression quantitative trait locus (eQTL) mapping. While trait-associated variants may operate in a cell-type specific manner, eQTL datasets for such cell-types may not always be available. We performed a genome-environment interaction (GxE) meta-analysis on data from 5,683 samples to infer the cell type specificity of whole blood cis-eQTLs. We demonstrate that this method is able to predict neutrophil and lymphocyte specific cis-eQTLs and replicate these predictions in independent cell-type specific datasets. Finally, we show that SNPs associated with Crohn's disease preferentially affect gene expression within neutrophils, including the archetypal NOD2 locus.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Crohn Disease / genetics
  • Gene Expression Regulation
  • Genome-Wide Association Study / methods
  • Humans
  • Lymphocytes / cytology*
  • Lymphocytes / metabolism
  • Neutrophils / cytology*
  • Neutrophils / metabolism
  • Nod2 Signaling Adaptor Protein / genetics
  • Nod2 Signaling Adaptor Protein / metabolism
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Principal Component Analysis
  • Quantitative Trait Loci*
  • Reproducibility of Results

Substances

  • NOD2 protein, human
  • Nod2 Signaling Adaptor Protein

Associated data

  • GEO/GSE20142
  • GEO/GSE33828
  • GEO/GSE36382
  • GEO/GSE48152
  • GEO/GSE48348

Grant support

DILGOM: JKe and SR were supported by funds from The European Community's Seventh Framework Programme (FP7/2007-2013) BioSHaRE, grant agreement 261433, SR was supported by funds from The European Community's Seventh Framework Programme (FP7/2007-2013) ENGAGE Consortium, grant agreement HEALTH-F4-2007- 201413", the Academy of Finland Center of Excellence in Complex Disease Genetics (grants 213506 and 129680), Academy of Finland (grant 251217), the Finnish foundation for Cardiovascular Research and the Sigrid Juselius Foundation. VS was supported by the Academy of Finland, grant number 139635 and Finnish Foundation for Cardiovascular Research. MPe was partly financially supported for this work by the Finnish Academy SALVE program ‘‘Pubgensense’’ 129322 and by grants from the Finnish Foundation for Cardiovascular Research. The DILGOM-study was supported by the Academy of Finland, grant # 118065. SHIP-TREND: SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Deutsche Forschungsgemeinschaft (DFG GRK840-D2), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania, and the network ‘Greifswald Approach to Individualized Medicine (GANI_MED)’ funded by the Federal Ministry of Education and Research (grant 03IS2061A). Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg, West Pomerania. Whole-body MR imaging was supported by a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg West Pomerania. The University of Greifswald is a member of the 'Center of Knowledge Interchange' program of the Siemens AG and the Caché Campus program of the InterSystems GmbH. The SHIP authors thank Mario Stanke for the opportunity to use his Server Cluster for the SNP imputation. EGCUT: EGCUT received financing by FP7 grants (201413, 245536), also received targeted financing from the Estonian Government (SF0180142s08) and direct funding from the Ministries of Research and Science and Social Affairs. EGCUT studies are funded by the University of Tartu in the framework of the Center of Translational Genomics and by the European Union through the European Regional Development Fund, in the framework of the Centre of Excellence in Genomics. Rotterdam Study: The Erasmus GRID Office, Erasmus MC Rotterdam, The Netherlands, and especially the national German MediGRID and Services@MediGRID part of the German D-Grid, both funded by the German Bundesministerium fuer Forschung und Technology under grants #01 AK 803 A-H and # 01 IG 07015 G for access to their grid resources. The authors thank the study participants and staff from the Rotterdam Study, the participating general practitioners and the pharmacists. The Rotterdam Study was funded by the European Commission (HEALTH-F2-2008-201865, GEFOS; HEALTH-F2-2008 35627, TREAT-OA 200800), the Netherlands Organization of Scientific Research NWO Investments (nos 175.010.2005.011, 911-03-012), the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Consortium for Healthy Aging (NCHA) (project nr. 050-060-810), an NWO VIDI grant (#917103521). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. Fehrmann: This study was supported by grants from the Celiac Disease Consortium (an innovative cluster approved by the Netherlands Genomics Initiative and partly funded by the Dutch Government (grant BSIK03009), the Netherlands Organization for Scientific Research (NWO-VICI grant 918.66.620, NWO-VENI grant 916.10.135 to LF), the Dutch Digestive Disease Foundation (MLDS WO11-30), and a Horizon Breakthrough grant from the Netherlands Genomics Initiative (grant 92519031 to LFr). This project was supported by the Prinses Beatrix Fonds, VSB fonds, H. Kersten and M. Kersten (Kersten Foundation), The Netherlands ALS Foundation, and J.R. van Dijk and the Adessium Foundation. The research leading to these results has received funding from the European Community’s Health Seventh Framework Programme (FP7/2007-2013) under grant agreement 259867. This study was supported by the BBMRI NL Functional Genomics Project. Funding for the project was provided by the Netherlands Organization for Scientific Research under award number 184021007, dated July 9, 2009 and made available as a Rainbow Project of the Biobanking and Biomolecular Research Infrastructure Netherlands (BBMRI–NL). DA was supported by the Centre for BioSystems Genomics (CBSG) and the Netherlands Consortium of Systems Biology (NCSB), both of which are part of the Netherlands Genomics Initiative / Netherlands Organisation for Scientific Research. InCHIANTI: InCHIANTI was supported by the Wellcome Trust 083270/Z/07/Z. The InCHIANTI study was supported by contract funding from the U.S. National Institute on Aging (NIA), and the research was supported in part by the Intramural Research Program, NIA, and National Institute of Health (NIH). ARW was supported by the Peninsula NIHR Clinical Research Facility. Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust. KORA F4: The KORA research platform and the KORA Augsburg studies are financed by the Helmholtz Zentrum München, German Research Center for Environmental Health, which is funded by the BMBF and by the State of Bavaria. We thank the field staff in Augsburg who were involved in the studies. The German Diabetes Center is funded by the German Federal Ministry of Health and the Ministry of School, Science and Research of the State of North-Rhine-Westphalia. The Diabetes Cohort Study was funded by a German Research Foundation project grant (DFG; RA 459/2-1). This study was supported in part by a grant from the BMBF to the German Center for Diabetes Research (DZD e.V.), by the DZHK (Deutsches Zentrum für Herz-Kreislauf-Forschung – German Centre for Cardiovascular Research) and by the BMBF funded Systems Biology of Metabotypes grant (SysMBo#0315494A). Additional support was given by the BMBF (National Genome Research Network NGFNplus Atherogenomics, 01GS0834) and the Leibniz Association (WGL Pakt für Forschung und Innovation). Oxford: This work was supported by the Wellcome Trust (Grants 074318 [JCK], 088891 [BPF], and 075491/Z/04 [core facilities Wellcome Trust Centre for Human Genetics]), the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013) / ERC Grant agreement no. 281824 (JCK) and the NIHR Oxford Biomedical Research Centre. Singapore Chinese functional genomics cohort: These studies were supported by A*STAR/SIgN core funding, and grants SIgN-06-006, SIgN-08-020 and SIgN-10-029. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.