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Gustav Smith, MD, PhD

Gustav Smith

Associate professor

Gustav Smith, MD, PhD

Mapping genetic determinants of 184 circulating proteins in 26,494 individuals to connect proteins and diseases

Author

  • Erin Macdonald-Dunlop
  • Lucija Klaric
  • Lasse Folkersen
  • Paul R H J Timmers
  • Stefan Gustafsson
  • Jing Hua Zhao
  • Niclas Eriksson
  • Anne Richmond
  • Stefan Enroth
  • Niklas Mattsson-Carlgren
  • Daria V Zhernakova
  • Martin Magnusson
  • J. Gustav Smith
  • Oskar Hansson
Show all

Summary, in English

We performed the largest genome-wide meta-analysis (GWAMA) (Max N=26,494) of the levels of 184 cardiovascular-related plasma protein levels to date and reported 592 independent loci (pQTL) associated with the level of at least one protein (1308 significant associations, median 6 per protein). We estimated that only between 8-37% of testable pQTL overlap with established expression quantitative trait loci (eQTL) using multiple methods, while 132 out of 1064 lead variants show evidence for transcription factor binding, and found that 75% of our pQTL are known DNA methylation QTL. We highlight the variation in genetic architecture between proteins and that proteins share genetic architecture with cardiometabolic complex traits. Using cis-instrument Mendelian randomisation (MR), we infer causal relationships for 11 proteins, recapitulating the previously reported relationship between PCSK9 and LDL cholesterol, replicating previous pQTL MR findings and discovering 16 causal relationships between protein levels and disease. Our MR results highlight IL2-RA as a candidate for drug repurposing for Crohn’s Disease as well as 2 novel therapeutic targets: IL-27 (Crohn’s disease) and TNFRSF14 (Inflammatory bowel disease, Multiple sclerosis and Ulcerative colitis). We have demonstrated the discoveries possible using our pQTL and highlight the potential of this work as a resource for genetic epidemiology.

Department/s

  • WCMM-Wallenberg Centre for Molecular Medicine
  • MultiPark: Multidisciplinary research focused on Parkinson´s disease
  • Brain Injury After Cardiac Arrest
  • Clinical Memory Research
  • Cardiovascular Research - Hypertension
  • EpiHealth: Epidemiology for Health
  • Heart Failure and Mechanical Support
  • Cardiovascular Epigenetics
  • Cardiology
  • EXODIAB: Excellence of Diabetes Research in Sweden
  • Molecular Epidemiology and Cardiology

Publishing year

2021-08-05

Language

English

Document type

Preprint

Publisher

medRxiv

Topic

  • Medical Genetics
  • Cardiac and Cardiovascular Systems

Status

Published

Research group

  • Brain Injury After Cardiac Arrest
  • Clinical Memory Research
  • Cardiovascular Research - Hypertension
  • Heart Failure and Mechanical Support
  • Cardiovascular Epigenetics
  • Molecular Epidemiology and Cardiology