Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits

• Published in: Nature communications Vol. 14; no. 1; p. 5062
• Main Authors: Brown, Andrew A., Fernandez-Tajes, Juan J., Hong, Mun-gwan, Brorsson, Caroline A., Koivula, Robert W., Davtian, David, Dupuis, Théo, Sartori, Ambra, Michalettou, Theodora-Dafni, Forgie, Ian M., Adam, Jonathan, Allin, Kristine H., Caiazzo, Robert, Cederberg, Henna, De Masi, Federico, Elders, Petra J. M., Giordano, Giuseppe N., Haid, Mark, Hansen, Torben, Hansen, Tue H., Hattersley, Andrew T., Heggie, Alison J., Howald, Cédric, Jones, Angus G., Kokkola, Tarja, Laakso, Markku, Mahajan, Anubha, Mari, Andrea, McDonald, Timothy J., McEvoy, Donna, Mourby, Miranda, Musholt, Petra B., Nilsson, Birgitte, Pattou, Francois, Penet, Deborah, Raverdy, Violeta, Ridderstråle, Martin, Romano, Luciana, Rutters, Femke, Sharma, Sapna, Teare, Harriet, ‘t Hart, Leen, Tsirigos, Konstantinos D., Vangipurapu, Jagadish, Vestergaard, Henrik, Brunak, Søren, Franks, Paul W., Frost, Gary, Grallert, Harald, Jablonka, Bernd, McCarthy, Mark I., Pavo, Imre, Pedersen, Oluf, Ruetten, Hartmut, Walker, Mark, Adamski, Jerzy, Schwenk, Jochen M., Pearson, Ewan R., Dermitzakis, Emmanouil T., Viñuela, Ana
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.08.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 38/43; 38/91; 45; 5' untranslated region; 631/114/2401; 631/208; 692/308/2056; 82/58; 82/80; adult; aged; Basic Medicine; biochemical analysis; Blood; cohort analysis; DNA extraction; donor; exon; fasting blood glucose level; female; functional enrichment analysis; Gene expression; gene linkage disequilibrium; Genetic analysis; genetic association; Genetic diversity; genetic heterogeneity; genetic regulation; Genetic variance; genetic variation; genome-wide association study; Genomics; genotyping; Heterogeneity; human; Humanities and Social Sciences; Humans; impaired glucose tolerance; Life Sciences; major clinical study; male; Medical and Health Sciences; Medical Genetics; Medicin och hälsovetenskap; Medicinsk genetik; Medicinska och farmaceutiska grundvetenskaper; messenger RNA; Metabolites; mitochondrion; multidisciplinary; Multifactorial Inheritance; Networks; non insulin dependent diabetes mellitus; pancreas islet; personnel; Phenotype; Phenotypes; phenotypic variation; plasma protein; Plasma proteins; Pleiotropy; protein; protein kinase Lck; Proteins; proteomics; quantitative trait locus; Research Personnel; RNA; RNA sequencing; RNA, Messenger; Science; Science (multidisciplinary); single nucleotide polymorphism; transcription factor; transcription regulation; Y chromosome
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-40569-3

We evaluate the shared genetic regulation of mRNA molecules, proteins and metabolites derived from whole blood from 3029 human donors. We find abundant allelic heterogeneity, where multiple variants regulate a particular molecular phenotype, and pleiotropy, where a single variant associates with multiple molecular phenotypes over multiple genomic regions. The highest proportion of share genetic regulation is detected between gene expression and proteins (66.6%), with a further median shared genetic associations across 49 different tissues of 78.3% and 62.4% between plasma proteins and gene expression. We represent the genetic and molecular associations in networks including 2828 known GWAS variants, showing that GWAS variants are more often connected to gene expression in trans than other molecular phenotypes in the network. Our work provides a roadmap to understanding molecular networks and deriving the underlying mechanism of action of GWAS variants using different molecular phenotypes in an accessible tissue. Many genetic variants have been associated with human traits, but the mechanism is often unknown. Here, the authors integrate local and distal genetic associations with multi-omics datasets to provide a roadmap to understand the underlying mechanisms of GWAS variants on complex traits.