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

ABSTRACT: 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.

SUBMITTER: Brown AA

PROVIDER: S-EPMC10442420 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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

Brown Andrew A AA Fernandez-Tajes Juan J JJ Hong Mun-Gwan MG Brorsson Caroline A CA Koivula Robert W RW Davtian David D Dupuis Théo T Sartori Ambra A Michalettou Theodora-Dafni TD Forgie Ian M IM Adam Jonathan J Allin Kristine H KH Caiazzo Robert R Cederberg Henna H De Masi Federico F Elders Petra J M PJM Giordano Giuseppe N GN Haid Mark M Hansen Torben T Hansen Tue H TH Hattersley Andrew T AT Heggie Alison J AJ Howald Cédric C Jones Angus G AG Kokkola Tarja T Laakso Markku M Mahajan Anubha A Mari Andrea A McDonald Timothy J TJ McEvoy Donna D Mourby Miranda M Musholt Petra B PB Nilsson Birgitte B Pattou Francois F Penet Deborah D Raverdy Violeta V Ridderstråle Martin M Romano Luciana L Rutters Femke F Sharma Sapna S Teare Harriet H 't Hart Leen L Tsirigos Konstantinos D KD Vangipurapu Jagadish J Vestergaard Henrik H Brunak Søren S Franks Paul W PW Frost Gary G Grallert Harald H Jablonka Bernd B McCarthy Mark I MI Pavo Imre I Pedersen Oluf O Ruetten Hartmut H Walker Mark M Adamski Jerzy J Schwenk Jochen M JM Pearson Ewan R ER Dermitzakis Emmanouil T ET Viñuela Ana A

Nature communications 20230821 1

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 gene ...[more]

PMID: 37604891

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Project description:Understanding the genetic contributions behind skeletal muscle composition and metabolism is of great interest in medicine and agriculture. Attempts to dissect these complex traits combine genome-wide genotyping, expression data analyses and network analyses. Weighted gene co-expression network analysis (WGCNA) groups genes into modules based on patterns of co-expression, which can be linked to phenotypes by correlation analysis of trait values and the module eigengenes, i.e. the first principal component of a given module. Network hub genes and regulators of the genes in the modules are likely to play an important role in the emergence of respective traits. In order to detect common regulators of genes in modules showing association with meat quality traits, we identified eQTL for each of these genes, including the highly connected hub genes. Additionally, the module eigengene values were used for association analyses in order to derive a joint eQTL for the respective module. Thereby major sites of orchestrated regulation of genes within trait-associated modules were detected as hotspots of eQTL of many genes of a module and of its eigengene. These sites harbor likely common regulators of genes in the modules. We exemplarily showed the consistent impact of candidate common regulators on the expression of members of respective modules by RNAi knockdown experiments. In fact, Cxcr7 was identified and validated as a regulator of genes in a module, which is involved in the function of defense response in muscle cells. Zfp36l2 was confirmed as a regulator of genes of a module related to cell death or apoptosis pathways. The integration of eQTL in module networks enabled to interpret the differentially-regulated genes from a systems perspective. By integrating genome-wide genomic and transcriptomic data, employing co-expression and eQTL analyses, the study revealed likely regulators that are involved in the fine-tuning and synchronization of genes with trait-associated expression.

Project description:BackgroundInsights into the genetic basis of complex traits and disease in both human and livestock species have been achieved over the past decade through detection of genetic variants in genome-wide association studies (GWAS). A majority of such variants were found located in noncoding genomic regions, and though the involvement of numerous regulatory elements (REs) has been predicted across multiple tissues in domesticated animals, their evolutionary conservation and effects on complex traits have not been fully elucidated, particularly in ruminants. Here, we systematically analyzed 137 epigenomic and transcriptomic datasets of six mammals, including cattle, sheep, goats, pigs, mice, and humans, and then integrated them with large-scale GWAS of complex traits.ResultsUsing 40 ChIP-seq datasets of H3K4me3 and H3K27ac, we detected 68,479, 58,562, 63,273, 97,244, 111,881, and 87,049 REs in the liver of cattle, sheep, goats, pigs, humans and mice, respectively. We then systematically characterized the dynamic functional landscapes of these REs by integrating multi-omics datasets, including gene expression, chromatin accessibility, and DNA methylation. We identified a core set (n = 6359) of ruminant-specific REs that are involved in liver development, metabolism, and immune processes. Genes with more complex cis-REs exhibited higher gene expression levels and stronger conservation across species. Furthermore, we integrated expression quantitative trait loci (eQTLs) and GWAS from 44 and 52 complex traits/diseases in cattle and humans, respectively. These results demonstrated that REs with different degrees of evolutionary conservation across species exhibited distinct enrichments for GWAS signals of complex traits.ConclusionsWe systematically annotated genome-wide functional REs in liver across six mammals and demonstrated the evolution of REs and their associations with transcriptional output and conservation. Detecting lineage-specific REs allows us to decipher the evolutionary and genetic basis of complex phenotypes in livestock and humans, which may benefit the discovery of potential biomedical models for functional variants and genes of specific human diseases.

Dataset Information

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

Publications

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

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