TY - JOUR T1 - Consequences of natural perturbations in the human plasma proteome JF - bioRxiv DO - 10.1101/134551 SP - 134551 AU - Benjamin B. Sun AU - Joseph C. Maranville AU - James E. Peters AU - David Stacey AU - James R. Staley AU - James Blackshaw AU - Stephen Burgess AU - Tao Jiang AU - Ellie Paige AU - Praveen Surendran AU - Clare Oliver-Williams AU - Mihir A. Kamat AU - Bram P. Prins AU - Sheri K. Wilcox AU - Erik S. Zimmerman AU - An Chi AU - Narinder Bansal AU - Sarah L. Spain AU - Angela M. Wood AU - Nicholas W. Morrell AU - John R. Bradley AU - Nebojsa Janjic AU - David J. Roberts AU - Willem H. Ouwehand AU - John A. Todd AU - Nicole Soranzo AU - Karsten Suhre AU - Dirk S. Paul AU - Caroline S. Fox AU - Robert M. Plenge AU - John Danesh AU - Heiko Runz AU - Adam S. Butterworth Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/05/05/134551.abstract N2 - Proteins are the primary functional units of biology and the direct targets of most drugs, yet there is limited knowledge of the genetic factors determining inter-individual variation in protein levels. Here we reveal the genetic architecture of the human plasma proteome, testing 10.6 million DNA variants against levels of 2,994 proteins in 3,301 individuals. We identify 1,927 genetic associations with 1,478 proteins, a 4-fold increase on existing knowledge, including trans associations for 1,104 proteins. To understand consequences of perturbations in plasma protein levels, we introduce an approach that links naturally occurring genetic variation with biological, disease, and drug databases. We provide insights into pathogenesis by uncovering the molecular effects of disease-associated variants. We identify causal roles for protein biomarkers in disease through Mendelian randomization analysis. Our results reveal new drug targets, opportunities for matching existing drugs with new disease indications, and potential safety concerns for drugs under development. ER -