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

Nat Commun. 2021 Dec 2;12(1):7042. doi: 10.1038/s41467-021-27387-1.

Authors

Grace Png^{1

2}, Andrei Barysenka³, Linda Repetto⁴, Pau Navarro⁵, Xia Shen^{4

6

7}, Maik Pietzner⁸, Eleanor Wheeler⁸, Nicholas J Wareham⁸, Claudia Langenberg^{8

9}, Emmanouil Tsafantakis¹⁰, Maria Karaleftheri¹¹, George Dedoussis¹², Anders Mälarstig^{13

14}, James F Wilson^{4

5}, Arthur Gilly³, Eleftheria Zeggini^{15

16}

Affiliations

¹ Institute of Translational Genomics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany. [email protected].
² TUM School of Medicine, Technical University of Munich and Klinikum Rechts der Isar, Munich, Germany. [email protected].
³ Institute of Translational Genomics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
⁴ Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, UK.
⁵ MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
⁶ Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, Guangzhou, China.
⁷ Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
⁸ MRC Epidemiology Unit, University of Cambridge, Cambridge, UK.
⁹ Computational Medicine, Berlin Institute of Health (BIH), Charité University Medicine, Berlin, Germany.
¹⁰ Anogia Medical Centre, Anogia, Greece.
¹¹ Echinos Medical Centre, Echinos, Greece.
¹² Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University of Athens, Athens, Greece.
¹³ Department of Medicine, Karolinska Institute, Solna, Sweden.
¹⁴ Emerging Science & Innovation, Pfizer Worldwide Research, Development and Medical, Cambridge, MA, USA.
¹⁵ Institute of Translational Genomics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany. [email protected].
¹⁶ TUM School of Medicine, Technical University of Munich and Klinikum Rechts der Isar, Munich, Germany. [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease / blood
Alzheimer Disease / diagnosis
Alzheimer Disease / genetics*
Alzheimer Disease / pathology
Biomarkers / blood
Cohort Studies
Gene Expression
Gene Ontology
Genetic Predisposition to Disease
Genome, Human
Humans
Membrane Glycoproteins / blood
Membrane Glycoproteins / genetics*
Mendelian Randomization Analysis
Molecular Sequence Annotation
Parkinson Disease / blood
Parkinson Disease / diagnosis
Parkinson Disease / genetics*
Parkinson Disease / pathology
Proteome / genetics
Proteome / metabolism
Quantitative Trait Loci
Scavenger Receptors, Class A / blood
Scavenger Receptors, Class A / genetics*
Schizophrenia / blood
Schizophrenia / diagnosis
Schizophrenia / genetics*
Schizophrenia / pathology
Sialic Acid Binding Ig-like Lectin 3 / blood
Sialic Acid Binding Ig-like Lectin 3 / genetics*
Whole Genome Sequencing

Substances

Biomarkers
CD33 protein, human
GPNMB protein, human
MSR1 protein, human
Membrane Glycoproteins
Proteome
Scavenger Receptors, Class A
Sialic Acid Binding Ig-like Lectin 3

Abstract

Publication types

MeSH terms

Substances

Grants and funding