AbCD-Net
Genetic variants affecting the risk of common diseases reside by and large outside the coding region. However so far, only a minor fraction of these could be shown to associate with variation in gene expression levels. Emerging evidence indicates that a significant fraction of disease-associated variants could exert its role by affecting splicing. Moreover, genetic studies on common diseases have been so far focusing – by design – on common genetic variants (found in > 5% of the population), leaving the larger number of rare variants – conferring potentially high risks – aside. It is therefore important to enable integrated genome-wide regulatory models of variants across the whole spectrum of allele frequency – particularly for those variants affecting splicing and expression levels.
Here, we set up a new research network, AbCD (Aberrant transcriptome influencing risk of common diseases), which brings together three e:Med groups with the required complementary expertise and resources to address this challenge: Julien Gagneur (mitOmics) has pioneered the detection of aberrant expression for diagnosis of rare diseases. Michael Ziller group (DiNGS) is developing computational methods to infer regulatory networks in order to interpret non-coding genetic variation. Heribert Schunkert (e:AtheroSysMed) overlooks globally the largest collection of individual level data on genomic variation and expression levels for a common disease, which enabled the discovery of numerous common and rare disease variants, as well as early attempts to integrate those into disease sub-networks.
Together, we will:
i) further exploit the methods to detect aberrant expression events
ii) integrate rare and common regulatory events on expression levels and isoform choices
iii) apply these methods to two major common diseases: coronary artery disease and schizophrenia
iv) provide software and training to the e:Med community
Publications
Aragam, K. G., T. Jiang, A. Goel, S. Kanoni, B. N. Wolford, D. S. Atri, E. M. Weeks, M. Wang, G. Hindy, W. Zhou, C. Grace, C. Roselli, N. A. Marston, F. K. Kamanu, I. Surakka, L. M. Venegas, P. Sherliker, S. Koyama, K. Ishigaki, B. O. Åsvold, M. R. Brown, B. Brumpton, P. S. de Vries, O. Giannakopoulou, P. Giardoglou, D. F. Gudbjartsson, U. Güldener, S. M. I. Haider, A. Helgadottir, M. Ibrahim, A. Kastrati, T. Kessler, T. Kyriakou, T. Konopka, L. Li, L. Ma, T. Meitinger, S. Mucha, M. Munz, F. Murgia, J. B. Nielsen, M. M. Nöthen, S. Pang, T. Reinberger, G. Schnitzler, D. Smedley, G. Thorleifsson, M. von Scheidt, J. C. Ulirsch, D. O. Arnar, N. P. Burtt, M. C. Costanzo, J. Flannick, K. Ito, D.-K. Jang, Y. Kamatani, A. V. Khera, I. Komuro, I. J. Kullo, L. A. Lotta, C. P. Nelson, R. Roberts, G. Thorgeirsson, U. Thorsteinsdottir, T. R. Webb, A. Baras, J. L. M. Björkegren, E. Boerwinkle, G. Dedoussis, H. Holm, K. Hveem, O. Melander, A. C. Morrison, M. Orho-Melander, L. S. Rallidis, A. Ruusalepp, M. S. Sabatine, K. Stefansson, P. Zalloua, P. T. Ellinor, M. Farrall, J. Danesh, C. T. Ruff, H. K. Finucane, J. C. Hopewell, R. Clarke, R. M. Gupta, J. Erdmann, N. J. Samani, H. Schunkert, H. Watkins, C. J. Willer, P. Deloukas, S. Kathiresan, and A. S. Butterworth (2022). "Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants." Nat Genet 54: 1803–1815. doi.org/10.1038/s41588-022-01233-6.
Chen, Z., and H. Schunkert (2021). "Genetics of coronary artery disease in the post-GWAS era." J Intern Med 290(5): 980-992. www.ncbi.nlm.nih.gov/pubmed/34237186.
de Jong, L., I. Bobeldijk-Pastorova, J. Erdmann, M. Bijker-Schreurs, H. Schunkert, J. A. Kuivenhoven, and A. J. van Gool (2020). "Sharing lessons learnt across European cardiovascular research consortia." Drug Discovery Today. www.sciencedirect.com/science/article/pii/S1359644620300350.
Dutsch, A., C. Graesser, F. Voll, S. Novacek, R. Eggerstedt, N. L. Armbruster, K.-L. Laugwitz, S. Cassese, H. Schunkert, G. Ndrepepa, A. Kastrati, T. Kessler, and H. B. Sager (2022). "Association of In‐Hospital Hemoglobin Drop With Decreased Myocardial Salvage and Increased Long‐Term Mortality in Patients With Acute ST‐Segment–Elevation Myocardial Infarction." J Am Heart Assoc. doi.org/10.1161/JAHA.121.024857.
Erdmann, J., T. Kessler, L. Munoz Venegas, and H. Schunkert (2018). "A decade of genome-wide association studies for coronary artery disease: the challenges ahead." Cardiovascular Research 114(9): 1241-1257. www.ncbi.nlm.nih.gov/pubmed/29617720.
Hettwer, J., J. Hinterdobler, B. Miritsch, M. A. Deutsch, X. Li, C. Mauersberger, A. Moggio, Q. Braster, H. Gram, A. A. B. Robertson, M. A. Cooper, O. Gross, M. Krane, C. Weber, W. Koenig, O. Soehnlein, N. H. Adamstein, P. Ridker, H. Schunkert, P. Libby, T. Kessler, and H. B. Sager (2021). "Interleukin-1beta suppression dampens inflammatory leukocyte production and uptake in atherosclerosis." Cardiovasc Res. www.ncbi.nlm.nih.gov/pubmed/34718444.
Hinterdobler, J., Schott, H. Jin, A. Meesmann, A.-L. Steinsiek, A.-S. Zimmermann, J. Wobst, P. Müller, C. Mauersberger, B. Vilne, A. Baecklund, C.-S. Chen, A. Moggio, Q. Braster, M. Molitor, M. Krane, W. E. Kempf, K.-H. Ladwig, M. Hristov, M. Hulsmans, I. Hilgendorf, C. Weber, P. Wenzel, C. Scheiermann, L. Maegdefessel, O. Soehnlein, P. Libby, M. Nahrendorf, H. Schunkert, T. Kessler, and H. B. Sager (2021). "Acute mental stress drives vascular inflammation and promotes plaque destabilization in mouse atherosclerosis." Eur Heart J 42(39): 4077–4088. doi.org/10.1093/eurheartj/ehab371.
Kessler, T., and H. Schunkert (2019). "Genetics of Recovery After Stroke." Circulation Research 124(1): 18-20. www.ncbi.nlm.nih.gov/pubmed/30605410.
Kopajtich, R., D. Smirnov, S. L. Stenton, S. Loipfinger, C. Meng, I. F. Scheller, P. Freisinger, R. Baski, R. Berutti, J. Behr, M. Bucher, F. Distelmaier, M. Gusic, M. Hempel, L. Kulterer, J. Mayr, T. Meitinger, C. Mertes, M. D. Metodiev, A. Nadel, A. Nasca, A. Ohtake, Y. Okazaki, R. Olsen, D. Piekutowska-Abramczuk, A. Rötig, R. Santer, D. Schindler, A. Slama, C. Staufner, T. Strom, P. Verloo, J.-C. von Kleist-Retzow, S. B. Wortmann, V. A. Yépez, C. Lamperti, D. Ghezzi, K. Murayama, C. Ludwig, J. Gagneur, and H. Prokisch (2021). "Integration of proteomics with genomics and transcriptomics increases the diagnostic rate of Mendelian disorders." medRxiv. doi.org/10.1101/2021.03.09.21253187.
Lechner, K., T. Kessler, and H. Schunkert (2020). "Should We Use Genetic Scores in the Determination of Treatment Strategies to Control Dyslipidemias?" Curr Cardiol Rep 22(11): 1–9. doi.org/10.1007/s11886-020-01408-9.
Li, L., Z. Chen, M. von Scheidt, S. Li, A. Steiner, U. Guldener, S. Koplev, A. Ma, K. Hao, C. Pan, A. J. Lusis, S. Pang, T. Kessler, R. Ermel, K. Sukhavasi, A. Ruusalepp, J. Gagneur, J. Erdmann, J. C. Kovacic, J. L. M. Bjorkegren, and H. Schunkert (2022). "Transcriptome-wide association study of coronary artery disease identifies novel susceptibility genes." Basic Res Cardiol 117(1): 6. www.ncbi.nlm.nih.gov/pubmed/35175464.
Li, L., S. Pang, L. Zeng, U. Güldener, and H. Schunkert (2021). "Genetically determined intelligence and coronary artery disease risk." Clin Res Cardiol 110(2): 211-219. doi.org/10.1007/s00392-020-01721-x.
Mauersberger, C., H. Schunkert, and H. B. Sager (2021). "Inflammation-Related Risk Loci in Genome-Wide Association Studies of Coronary Artery Disease." Cells 10(2): 440. doi.org/10.3390/cells10020440.
Meyer-Lindemann, U., C. Mauersberger, A.-C. Schmidt, A. Moggio, J. Hinterdobler, X. Li, D. Khangholi, J. Hettwer, C. Gräßer, A. Dutsch, H. Schunkert, T. Kessler, and H. B. Sager (2022). "Colchicine Impacts Leukocyte Trafficking in Atherosclerosis and Reduces Vascular Inflammation." Front Immunol 0. doi.org/10.3389/fimmu.2022.898690.
Moggio, A., H. Schunkert, T. Kessler, and H. B. Sager (2022). "Quo Vadis? Immunodynamics of Myeloid Cells after Myocardial Infarction." Int J Mol Sci 23(24): 15814. doi.org/10.3390/ijms232415814.
Murdock, D. R., H. Dai, L. C. Burrage, J. A. Rosenfeld, S. Ketkar, M. F. Müller, V. A. Yépez, J. Gagneur, P. Liu, S. Chen, M. Jain, G. Zapata, C. A. Bacino, H.-T. Chao, P. Moretti, W. J. Craigen, N. A. Hanchard, and B. Lee (2021). "Transcriptome-directed analysis for Mendelian disease diagnosis overcomes limitations of conventional genomic testing." J Clin Invest 131(1). doi.org/10.1172/JCI141500.
Ntalla, I., S. Kanoni, L. Zeng, O. Giannakopoulou, J. Danesh, H. Watkins, N. J. Samani, P. Deloukas, H. Schunkert, and U. K. B. C. C. C. W. Group (2019). "Genetic Risk Score for Coronary Disease Identifies Predispositions to Cardiovascular and Noncardiovascular Diseases." J Am Coll Cardiol 73(23): 2932-2942. www.ncbi.nlm.nih.gov/pubmed/31196449.
Pang, S., L. Yengo, C. P. Nelson, F. Bourier, L. Zeng, L. Li, T. Kessler, J. Erdmann, R. Mägi, K. Läll, A. Metspalu, B. Mueller-Myhsok, N. J. Samani, P. M. Visscher, and H. Schunkert (2022). "Genetic and modifiable risk factors combine multiplicatively in common disease." Clinical Research in Cardiology. doi.org/10.1007/s00392-022-02081-4.
Pinto-Sietsma, S.-J., M. Flossdorf, V. R. Buchholz, J. Offerhaus, H. Bleijendaal, M. Beudel, P. G. A. Volders, R. M. A. ter Bekke, T. Dormans, P.-P. Zwetsloot, P. de Jager, S. Massberg, P. Rämer, C. Wendtner, E. Hoffmann, K. Rothe, S. Feihl, T. Kessler, Y. M. Pinto, and H. Schunkert (2020). "Antihypertensive drugs in COVID-19 infection." Eur Heart J Cardiovasc Pharmacother. doi.org/10.1093/ehjcvp/pvaa058.
Schunkert, H. (2020). "Editorial commentary: Genome-wide association study for coronary artery disease-Past, present and future." TRENDS IN CARDIOVASCULAR MEDICINE 30(6): 335–337. doi.org/10.1016/j.tcm.2019.09.001.
Schunkert, H., and M. Mayr (2022). "Linking Genetics and Proteomics: Gene-Protein Associations Built on Diversity." Circulation. www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.121.058303.
Schunkert, H., and N. J. Samani (2018). "Into the great wide open: 10 years of genome-wide association studies." Cardiovascular Research 114(9): 1189-1191. www.ncbi.nlm.nih.gov/pubmed/29688283.
Schunkert, H., M. von Scheidt, T. Kessler, B. Stiller, L. Zeng, and B. Vilne (2018). "Genetics of coronary artery disease in the light of genome-wide association studies." Clinical Research in Cardiology: Official Journal of the German Cardiac Society 107(Suppl 2): 2-9. www.ncbi.nlm.nih.gov/pubmed/30022276.
von Scheidt, M., Y. Zhao, T. Q. de Aguiar Vallim, N. Che, M. Wierer, M. M. Seldin, O. Franzén, Z. Kurt, S. Pang, D. Bongiovanni, M. Yamamoto, P. A. Edwards, A. Ruusalepp, J. C. Kovacic, M. Mann, J. L. M. Björkegren, A. J. Lusis, X. Yang, and H. Schunkert (2021). "The Transcription Factor MAFF Regulates an Atherosclerosis Relevant Network Connecting Inflammation and Cholesterol Metabolism." Circulation 143(18): 1809-1823. doi.org/10.1161/CIRCULATIONAHA.120.050186.
Yang, C., F. Starnecker, S. Pang, Z. Chen, U. Güldener, L. Li, M. Heinig, and H. Schunkert (2021). "Polygenic risk for coronary artery disease in the Scottish and English population." BMC Cardiovasc Disord 21(1): 1–9. doi.org/10.1186/s12872-021-02398-4.
Yépez, V. A., C. Mertes, M. F. Müller, D. Klaproth-Andrade, L. Wachutka, L. Frésard, M. Gusic, I. F. Scheller, P. F. Goldberg, H. Prokisch, and J. Gagneur (2021). "Detection of aberrant gene expression events in RNA sequencing data." Nature Protocols 16(2): 1276–1296. doi.org/10.1038/s41596-020-00462-5.
Zeng, L., S. Moser, N. Mirza-Schreiber, C. Lamina, S. Coassin, C. P. Nelson, T. Annilo, O. Franzén, M. E. Kleber, S. Mack, T. F. M. Andlauer, B. Jiang, B. Stiller, L. Li, C. Willenborg, M. Munz, T. Kessler, A. Kastrati, K.-L. Laugwitz, J. Erdmann, S. Moebus, M. M. Nöthen, A. Peters, K. Strauch, M. Müller-Nurasyid, C. Gieger, T. Meitinger, E. Steinhagen-Thiessen, W. März, A. Metspalu, J. L. M. Björkegren, N. J. Samani, F. Kronenberg, B. Müller-Myhsok, and H. Schunkert (2022). "Cis-epistasis at the LPA locus and risk of cardiovascular diseases." Cardiovasc Res 118(4): 1088–1102. doi.org/10.1093/cvr/cvab136.
Zeng, L., H. A. Talukdar, S. Koplev, C. Giannarelli, T. Ivert, L. M. Gan, A. Ruusalepp, E. E. Schadt, J. C. Kovacic, A. J. Lusis, T. Michoel, H. Schunkert, and J. L. M. Bjorkegren (2019). "Contribution of Gene Regulatory Networks to Heritability of Coronary Artery Disease." J Am Coll Cardiol 73(23): 2946-2957. www.ncbi.nlm.nih.gov/pubmed/31196451.