Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals

Folkersen, L. and Gustafsson, S. and Wang, Q. and Hansen, D.H. and Hedman, Å.K. and Schork, A. and Page, K. and Zhernakova, D.V. and Wu, Y. and Peters, J. and Eriksson, N. and Bergen, S.E. and Boutin, T.S. and Bretherick, A.D. and Enroth, S. and Kalnapenkis, A. and Gådin, J.R. and Suur, B.E. and Chen, Y. and Matic, L. and Gale, J.D. and Lee, J. and Zhang, W. and Quazi, A. and Ala-Korpela, M. and Choi, S.H. and Claringbould, A. and Danesh, J. and Davey Smith, G. and de Masi, F. and Elmståhl, S. and Engström, G. and Fauman, E. and Fernandez, C. and Franke, L. and Franks, P.W. and Giedraitis, V. and Haley, C. and Hamsten, A. and Ingason, A. and Johansson, Å. and Joshi, P.K. and Lind, L. and Lindgren, C.M. and Lubitz, S. and Palmer, T. and Macdonald-Dunlop, E. and Magnusson, M. and Melander, O. and Michaelsson, K. and Morris, A.P. and Mägi, R. and Nagle, M.W. and Nilsson, P.M. and Nilsson, J. and Orho-Melander, M. and Polasek, O. and Prins, B. and Pålsson, E. and Qi, T. and Sjögren, M. and Sundström, J. and Surendran, P. and Võsa, U. and Werge, T. and Wernersson, R. and Westra, H.-J. and Yang, J. and Zhernakova, A. and Ärnlöv, J. and Fu, J. and Smith, J.G. and Esko, T. and Hayward, C. and Gyllensten, U. and Landen, M. and Siegbahn, A. and Wilson, J.F. and Wallentin, L. and Butterworth, A.S. and Holmes, M.V. and Ingelsson, E. and Mälarstig, A. (2020) Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals. Nature Metabolism, 2 (10). pp. 1135-1148.

Abstract

Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.