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

Brown AA, Fernandez-Tajes JJ, Hong MG, Brorsson CA, Koivula RW, Davtian D, Dupuis T, Sartori A, Michalettou TD, Forgie IM, Adam J, Allin KH, Caiazzo R, Cederberg H, De Masi F, Elders PJM, Giordano GN, Haid M, Hansen T, Hansen TH, Hattersley AT, Heggie AJ, Howald C, Jones AG, Kokkola T, Laakso M, Mahajan A, Mari A, McDonald TJ, McEvoy D, Mourby M, Musholt PB, Nilsson B, Pattou F, Penet D, Raverdy V, Ridderstråle M, Romano L, Rutters F, Sharma S, Teare H, 't Hart L, Tsirigos KD, Vangipurapu J, Vestergaard H, Brunak S, Franks PW, Frost G, Grallert H, Jablonka B, McCarthy MI, Pavo I, Pedersen O, Ruetten H, Walker M, DIRECT Consortium , Adamski J, Schwenk JM, Pearson ER, Dermitzakis ET, Viñuela A

Nat Commun 14 (1) 5062 [2023-08-21; online 2023-08-21]

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.

PubMed 37604891

DOI 10.1038/s41467-023-40569-3

Crossref 10.1038/s41467-023-40569-3

pmc: PMC10442420
pii: 10.1038/s41467-023-40569-3