Mapping the proteo-genomic convergence of human diseases

• Published in: Science (American Association for the Advancement of Science) Vol. 374; no. 6569; p. eabj1541
• Main Authors: Pietzner, Maik, Wheeler, Eleanor, Carrasco-Zanini, Julia, Cortes, Adrian, Koprulu, Mine, Wörheide, Maria A., Oerton, Erin, Cook, James, Stewart, Isobel D., Kerrison, Nicola D., Luan, Jian’an, Raffler, Johannes, Arnold, Matthias, Arlt, Wiebke, O’Rahilly, Stephen, Kastenmüller, Gabi, Gamazon, Eric R., Hingorani, Aroon D., Scott, Robert A., Wareham, Nicholas J., Langenberg, Claudia
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 12.11.2021
• Subjects: Aging; Alternative Splicing; Alzheimer's disease; Annotations; Biology; Blood Proteins - genetics; Blood Proteins - metabolism; Calculi; Cholesterol; Connective tissue; Connective Tissue Diseases - genetics; Connective tissues; Context; Convergence; COVID-19; COVID-19 - genetics; Crystallization; Disease - etiology; Disease - genetics; Disorders; Drug Development; Endometrial cancer; Endometrium; Etiology; Extracellular matrix; Female; Fibrosis; Gallstones - genetics; Gene expression; Gene mapping; Genes; Genetic Association Studies; Genetic diversity; Genetic variance; Genetic Variation; Genome, Human; Genome-Wide Association Study; Genomes; Genomics; Genotype & phenotype; Humans; Internet; Internet resources; Interrogation; Male; Matrix protein; Medical research; Mode of action; Mutation; Neurodegenerative diseases; Peptide mapping; Phenotype; Phenotypes; Plasma; Plasma proteins; Proteins; Proteins - genetics; Proteins - metabolism; Proteome; Proteomes; Proteomics; Quantitative Trait Loci; Sex Characteristics; Splicing; Therapeutic targets
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.abj1541

Many diseases are at least partially due to genetic causes that are not always understood or targetable with specific treatments. To provide insight into the biology of various human diseases as well as potential leads for therapeutic development, Pietzner et al . undertook detailed, genome-wide proteogenomic mapping. The authors analyzed thousands of connections between potential disease-associated mutations, specific proteins, and medical conditions, thereby providing a detailed map for use by future researchers. They also supplied some examples in which they applied their approach to medical contexts as varied as connective tissue disorders, gallstones, and COVID-19 infections, sometimes even identifying single genes that play roles in multiple clinical scenarios. —YN A detailed map of genes, proteins, and diseases helps to provide biological insights and indicate possible therapeutic directions. 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.