TY - JOUR
T1 - Multiomic blood correlates of genetic risk identify presymptomatic disease alterations
AU - Wainberg, Michael
AU - Magis, Andrew T.
AU - Earls, John C.
AU - Lovejoy, Jennifer C.
AU - Sinnott-Armstrong, Nasa
AU - Omenn, Gilbert S.
AU - Hood, Leroy
AU - Price, Nathan D.
N1 - Funding Information:
We gratefully acknowledge Allison Kudla for the graphic design of Fig. 1. We also thank Noa Rappaport, Tomasz Wilmanski, Sergey Kornilov, James Yurkovich, Shizhen Qin, and other members of the L.H.-N.D.P. laboratory and the Institute for Systems Biology for helpful discussions and Nik Schork for a critical reading of the paper. This research was supported by the National Institute on Aging through the Longevity Consortium (Grant 2U19AG023122-11A1 [to N.D.P.]).
Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.
PY - 2020/9/1
Y1 - 2020/9/1
N2 - Transitions from health to disease are characterized by dysregulation of biological networks under the influence of genetic and environmental factors, often over the course of years to decades before clinical symptoms appear. Understanding these dynamics has important implications for preventive medicine. However, progress has been hindered both by the difficulty of identifying individuals who will eventually go on to develop a particular disease and by the inaccessibility of most disease-relevant tissues in living individuals. Here we developed an alternative approach using polygenic risk scores (PRSs) based on genome-wide association studies (GWAS) for 54 diseases and complex traits coupled with multiomic profiling and found that these PRSs were associated with 766 detectable alterations in proteomic, metabolomic, and standard clinical laboratory measurements (clinical labs) from blood plasma across several thousand mostly healthy individuals. We recapitulated a variety of known relationships (e.g., glutamatergic neurotransmission and inflammation with depression, IL-33 with asthma) and found associations directly suggesting therapeutic strategies (e.g., Ω-6 supplementation and IL-13 inhibition for amyotrophic lateral sclerosis) and influences on longevity (leukemia inhibitory factor, ceramides). Analytes altered in high-genetic-risk individuals showed concordant changes in disease cases, supporting the notion that PRS-associated analytes represent presymptomatic disease alterations. Our results provide insights into the molecular pathophysiology of a range of traits and suggest avenues for the prevention of health-to-disease transitions.
AB - Transitions from health to disease are characterized by dysregulation of biological networks under the influence of genetic and environmental factors, often over the course of years to decades before clinical symptoms appear. Understanding these dynamics has important implications for preventive medicine. However, progress has been hindered both by the difficulty of identifying individuals who will eventually go on to develop a particular disease and by the inaccessibility of most disease-relevant tissues in living individuals. Here we developed an alternative approach using polygenic risk scores (PRSs) based on genome-wide association studies (GWAS) for 54 diseases and complex traits coupled with multiomic profiling and found that these PRSs were associated with 766 detectable alterations in proteomic, metabolomic, and standard clinical laboratory measurements (clinical labs) from blood plasma across several thousand mostly healthy individuals. We recapitulated a variety of known relationships (e.g., glutamatergic neurotransmission and inflammation with depression, IL-33 with asthma) and found associations directly suggesting therapeutic strategies (e.g., Ω-6 supplementation and IL-13 inhibition for amyotrophic lateral sclerosis) and influences on longevity (leukemia inhibitory factor, ceramides). Analytes altered in high-genetic-risk individuals showed concordant changes in disease cases, supporting the notion that PRS-associated analytes represent presymptomatic disease alterations. Our results provide insights into the molecular pathophysiology of a range of traits and suggest avenues for the prevention of health-to-disease transitions.
KW - Metabolomics
KW - Polygenic risk scores
KW - Presymptomatic disease
KW - Proteomics
UR - http://www.scopus.com/inward/record.url?scp=85090507577&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85090507577&partnerID=8YFLogxK
U2 - 10.1073/pnas.2001429117
DO - 10.1073/pnas.2001429117
M3 - Article
C2 - 32817414
AN - SCOPUS:85090507577
SN - 0027-8424
VL - 117
SP - 21813
EP - 21820
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 35
ER -