Mapping the serum proteome to neurological diseases using whole genome sequencing

Grace Png; Andrei Barysenka; Linda Repetto; Pau Navarro; Xia Shen; Maik Pietzner; Eleanor Wheeler; Nicholas J Wareham; Claudia Langenberg; Emmanouil Tsafantakis; Maria Karaleftheri; George Dedoussis; Anders Mälarstig; James F Wilson; Arthur Gilly; Eleftheria Zeggini

doi:10.1038/s41467-021-27387-1

Mapping the serum proteome to neurological diseases using whole genome sequencing

Grace Png, Andrei Barysenka, Linda Repetto, Pau Navarro, Xia Shen, Maik Pietzner, Eleanor Wheeler, Nicholas J Wareham, Claudia Langenberg, Emmanouil Tsafantakis, Maria Karaleftheri, George Dedoussis, Anders Mälarstig, James F Wilson, Arthur Gilly, Eleftheria Zeggini

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Abstract / Description of output

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.

Original language	English
Pages (from-to)	7042
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-27387-1
Publication status	Published - 2 Dec 2021

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Mapping the serum proteome to neurological diseases using whole genome sequencingFinal published version, 2.66 MBLicence: Creative Commons: Attribution (CC-BY)

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Png, G., Barysenka, A., Repetto, L., Navarro, P., Shen, X., Pietzner, M., Wheeler, E., Wareham, N. J., Langenberg, C., Tsafantakis, E., Karaleftheri, M., Dedoussis, G., Mälarstig, A., Wilson, J. F., Gilly, A., & Zeggini, E. (2021). Mapping the serum proteome to neurological diseases using whole genome sequencing. Nature Communications, 12(1), 7042. https://doi.org/10.1038/s41467-021-27387-1

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abstract = "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.",

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Png, G, Barysenka, A, Repetto, L, Navarro, P, Shen, X, Pietzner, M, Wheeler, E, Wareham, NJ, Langenberg, C, Tsafantakis, E, Karaleftheri, M, Dedoussis, G, Mälarstig, A, Wilson, JF, Gilly, A & Zeggini, E 2021, 'Mapping the serum proteome to neurological diseases using whole genome sequencing', Nature Communications, vol. 12, no. 1, pp. 7042. https://doi.org/10.1038/s41467-021-27387-1

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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

PY - 2021/12/2

Y1 - 2021/12/2

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.

U2 - 10.1038/s41467-021-27387-1

DO - 10.1038/s41467-021-27387-1

M3 - Article

C2 - 34857772

SN - 2041-1723

VL - 12

SP - 7042

JO - Nature Communications

JF - Nature Communications

IS - 1

ER -

Mapping the serum proteome to neurological diseases using whole genome sequencing

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