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Mapping the proteo-genomic convergence of human diseases.

Accepted version
Peer-reviewed

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Article

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Abstract

Characterization of the genetic regulation of proteins is essential for understanding disease etiology and developing therapies. We identified 10,674 genetic associations for 3892 plasma proteins to create a cis-anchored gene-protein-disease map of 1859 connections that highlights strong cross-disease biological convergence. This proteo-genomic map provides a framework to connect etiologically related diseases, to provide biological context for new or emerging disorders, and to integrate different biological domains to establish mechanisms for known gene-disease links. Our results identify proteo-genomic connections within and between diseases and establish the value of cis-protein variants for annotation of likely causal disease genes at loci identified in genome-wide association studies, thereby addressing a major barrier to experimental validation and clinical translation of genetic discoveries.

Description

Keywords

Aging, Alternative Splicing, Blood Proteins, COVID-19, Connective Tissue Diseases, Disease, Drug Development, Female, Gallstones, Genetic Association Studies, Genetic Variation, Genome, Human, Genome-Wide Association Study, Genomics, Humans, Internet, Male, Phenotype, Proteins, Proteome, Quantitative Trait Loci, Sex Characteristics

Journal Title

Science

Conference Name

Journal ISSN

0036-8075
1095-9203

Volume Title

Publisher

American Association for the Advancement of Science (AAAS)

Rights

All rights reserved
Sponsorship
MRC (MC_UU_00006/1)
MRC (MC_PC_13046)
Medical Research Council (MC_UU_12015/1)
Wellcome Trust (214274/Z/18/Z)
Medical Research Council (MC_PC_13046)
The Fenland Study (10.22025/2017.10.101.00001) is funded by the Medical Research Council (MC_UU_12015/1). We further acknowledge support for genomics from the Medical Research Council (MC_PC_13046). ERG is supported by the National Institutes of Health (NIH) Awards R35HG010718, R01HG011138, R01GM140287, and NIH/NIA AG068026. MAW, MA, and GK are supported by grants from the National Institute on Aging (NIA): U01 AG061359, RF1 AG057452, and RF1 AG059093). JCZ is supported by a 4-year Wellcome Trust PhD Studentship and the Cambridge Trust; MK is supported by a Gates Fellowship; CL, EW, MP, JL, EO, IS, NK, and NJW are funded by the Medical Research Council (MC_UU_00006/1 - Aetiology and Mechanisms). This work was supported in part by the UKRI/NIHR Strategic Priorities Award in Multimorbidity Research for the Multimorbidity Mechanism and Therapeutics Research Collaborative (MR/V033867/1).