TY - JOUR
T1 - Mapping the serum proteome to neurological diseases using whole genome sequencing
AU - Png, Grace
AU - Barysenka, Andrei
AU - Repetto, Linda
AU - Navarro, Pau
AU - Shen, Xia
AU - Pietzner, Maik
AU - Wheeler, Eleanor
AU - Wareham, Nicholas J.
AU - Langenberg, Claudia
AU - Tsafantakis, Emmanouil
AU - Karaleftheri, Maria
AU - Dedoussis, George
AU - Mälarstig, Anders
AU - Wilson, James F.
AU - Gilly, Arthur
AU - Zeggini, Eleftheria
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - Despite the increasing global burden of neurological disorders, there is a lack of effective diagnostic and therapeutic biomarkers. Proteins are often dysregulated in disease and have a strong genetic component. Here, we carry out a protein quantitative trait locus analysis of 184 neurologically-relevant proteins, using whole genome sequencing data from two isolated population-based cohorts (N = 2893). In doing so, we elucidate the genetic landscape of the circulating proteome and its connection to neurological disorders. We detect 214 independently-associated variants for 107 proteins, the majority of which (76%) are cis-acting, including 114 variants that have not been previously identified. Using two-sample Mendelian randomisation, we identify causal associations between serum CD33 and Alzheimer’s disease, GPNMB and Parkinson’s disease, and MSR1 and schizophrenia, describing their clinical potential and highlighting drug repurposing opportunities.
AB - Despite the increasing global burden of neurological disorders, there is a lack of effective diagnostic and therapeutic biomarkers. Proteins are often dysregulated in disease and have a strong genetic component. Here, we carry out a protein quantitative trait locus analysis of 184 neurologically-relevant proteins, using whole genome sequencing data from two isolated population-based cohorts (N = 2893). In doing so, we elucidate the genetic landscape of the circulating proteome and its connection to neurological disorders. We detect 214 independently-associated variants for 107 proteins, the majority of which (76%) are cis-acting, including 114 variants that have not been previously identified. Using two-sample Mendelian randomisation, we identify causal associations between serum CD33 and Alzheimer’s disease, GPNMB and Parkinson’s disease, and MSR1 and schizophrenia, describing their clinical potential and highlighting drug repurposing opportunities.
UR - https://www.scopus.com/pages/publications/85120851674
U2 - 10.1038/s41467-021-27387-1
DO - 10.1038/s41467-021-27387-1
M3 - Article
C2 - 34857772
AN - SCOPUS:85120851674
SN - 2041-1723
VL - 12
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 7042
ER -