TY - JOUR
T1 - Associations of carotid intima media thickness with gene expression in whole blood and genetically predicted gene expression across 48 tissues
AU - Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Subclinical Working Group
AU - Castaneda, Andy B.
AU - Petty, Lauren E.
AU - Scholz, Markus
AU - Jansen, Rick
AU - Weiss, Stefan
AU - Zhang, Xiaoling
AU - Schramm, Katharina
AU - Beutner, Frank
AU - Kirsten, Holger
AU - Schminke, Ulf
AU - Hwang, Shih Jen
AU - Marzi, Carola
AU - Dhana, Klodian
AU - Seldenrijk, Adrie
AU - Krohn, Knut
AU - Homuth, Georg
AU - Wolf, Petra
AU - Peters, Marjolein J.
AU - Dörr, Marcus
AU - Peters, Annette
AU - van Meurs, Joyce B.J.
AU - Uitterlinden, André G.
AU - Kavousi, Maryam
AU - Levy, Daniel
AU - Herder, Christian
AU - van Grootheest, Gerard
AU - Waldenberger, Melanie
AU - Meisinger, Christa
AU - Rathmann, Wolfgang
AU - Thiery, Joachim
AU - Polak, Joseph
AU - Koenig, Wolfgang
AU - Seissler, Jochen
AU - Bis, Joshua C.
AU - Franceshini, Nora
AU - Giambartolomei, Claudia
AU - Hofman, Albert
AU - Franco, Oscar H.
AU - Penninx, Brenda W.J.H.
AU - Prokisch, Holger
AU - Völzke, Henry
AU - Loeffler, Markus
AU - O'Donnell, Christopher J.
AU - Below, Jennifer E.
AU - Dehghan, Abbas
AU - de Vries, Paul S.
N1 - Funding Information: This work was supported by American Heart Association Grant [grant numbers 17POST33350042, 18CDA34110116 to P.V.]; National Heart, Lung, and Blood Institute [grant numbers R01HL146860 to P.V, R01HL142302 to J.B. and L.P., R01HL105756]; National Institute of Aging [grant number R01AG061351 to J.B. and L.P]. The LIFE-Adult study, LIFE-Heart study, and the Leipzig Research Centre for Civilization Diseases was supported by the European Union; the European Regional Development Fund; and the Free State of Saxony [project numbers 713-241202, 713-241202, 14505/2470, 14575/2470]. The Framingham Heart Study of the National Heart, Lung, and Blood Institute of the US National Institutes of Health is supported by the Boston University School of Medicine; the Systems Approach to Biomarker Research in Cardiovascular Disease (SABRe) project; the National Heart, Lung and Blood Institute Division of Intramural Research; and the United States National Institute of Health [contract N01-HC-25195]. The Cooperative Health Research in the Region of Augsburg (KORA F4) study and the Helmholtz Zentrum München – German Research Center for Environmental Health were supported by the German Federal Ministry of Education and Research; the State of Bavaria; the Munich Center of Health Sciences, Ludwig-Maximilians-Universität LMUinnovativ grant; the German Federal Ministry of Health (BMG); the Ministry of Culture and Science of the State North Rhine-Westphalia; and the German Center for Diabetes Research which is funded by the and the European Union Seventh Framework Programme [grant numbers n°603288, n°313010, n°602736]. The Netherlands Study of Depression and Anxiety is supported by VU University Medical Center; GGZ ingest; Arkin; Leiden University Medical Center; GGZ Rivierduinen; University Medical Center Groningen; Lentis; GGZ Friesland; GGZ Drenthe; Scientific Institute for Quality of Healthcare Netherlands Institute for Health Services Research; Netherlands Institute of Mental Health and Addiction (Trimbos Institute); the Netherlands Heart Foundation [grant number 2006B258]; the US National Institute of Mental Health [grant number RC2 MH089951]; and the Geestkracht program of the Netherlands Organization for Health Research and Development [grant number 10-000-1002]. The Rotterdam Study is supported by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus Medical Center; Erasmus Medical Center and Erasmus University Rotterdam; the Netherlands Organization for the 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. The Study of Health in Pomerania – TREND is funded by Siemens Healthcare; the Federal State of Mecklenburg, West Pomerania; the `Center of Knowledge Interchange' program of the Siemens AG; and the Federal Ministry of Education and Research [grant numbers 01ZZ9603, 01ZZ0103, 01ZZ0403, 03IS2061A, 03ZIK012]. Publisher Copyright: © 2021 Published by Oxford University Press 2021.
PY - 2022/4/1
Y1 - 2022/4/1
N2 - Carotid intima media thickness (cIMT) is a biomarker of subclinical atherosclerosis and a predictor of future cardiovascular events. Identifying associations between gene expression levels and cIMT may provide insight to atherosclerosis etiology. Here, we use two approaches to identify associations between mRNA levels and cIMT: differential gene expression analysis in whole blood and S-PrediXcan. We used microarrays to measure genome-wide whole blood mRNA levels of 5647 European individuals from four studies. We examined the association of mRNA levels with cIMT adjusted for various potential confounders. Significant associations were tested for replication in three studies totaling 3943 participants. Next, we applied S-PrediXcan to summary statistics from a cIMT genome-wide association study (GWAS) of 71 128 individuals to estimate the association between genetically determined mRNA levels and cIMT and replicated these analyses using S-PrediXcan on an independent GWAS on cIMT that included 22 179 individuals from the UK Biobank. mRNA levels of TNFAIP3, CEBPD and METRNL were inversely associated with cIMT, but these associations were not significant in the replication analysis. S-PrediXcan identified associations between cIMT and genetically determined mRNA levels for 36 genes, of which six were significant in the replication analysis, including TLN2, which had not been previously reported for cIMT. There was weak correlation between our results using differential gene expression analysis and S-PrediXcan. Differential expression analysis and S-PrediXcan represent complementary approaches for the discovery of associations between phenotypes and gene expression. Using these approaches, we prioritize TNFAIP3, CEBPD, METRNL and TLN2 as new candidate genes whose differential expression might modulate cIMT.
AB - Carotid intima media thickness (cIMT) is a biomarker of subclinical atherosclerosis and a predictor of future cardiovascular events. Identifying associations between gene expression levels and cIMT may provide insight to atherosclerosis etiology. Here, we use two approaches to identify associations between mRNA levels and cIMT: differential gene expression analysis in whole blood and S-PrediXcan. We used microarrays to measure genome-wide whole blood mRNA levels of 5647 European individuals from four studies. We examined the association of mRNA levels with cIMT adjusted for various potential confounders. Significant associations were tested for replication in three studies totaling 3943 participants. Next, we applied S-PrediXcan to summary statistics from a cIMT genome-wide association study (GWAS) of 71 128 individuals to estimate the association between genetically determined mRNA levels and cIMT and replicated these analyses using S-PrediXcan on an independent GWAS on cIMT that included 22 179 individuals from the UK Biobank. mRNA levels of TNFAIP3, CEBPD and METRNL were inversely associated with cIMT, but these associations were not significant in the replication analysis. S-PrediXcan identified associations between cIMT and genetically determined mRNA levels for 36 genes, of which six were significant in the replication analysis, including TLN2, which had not been previously reported for cIMT. There was weak correlation between our results using differential gene expression analysis and S-PrediXcan. Differential expression analysis and S-PrediXcan represent complementary approaches for the discovery of associations between phenotypes and gene expression. Using these approaches, we prioritize TNFAIP3, CEBPD, METRNL and TLN2 as new candidate genes whose differential expression might modulate cIMT.
UR - http://www.scopus.com/inward/record.url?scp=85128161497&partnerID=8YFLogxK
U2 - https://doi.org/10.1093/hmg/ddab236
DO - https://doi.org/10.1093/hmg/ddab236
M3 - Article
C2 - 34788810
SN - 0964-6906
VL - 31
SP - 1171
EP - 1182
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 7
ER -