Genetic correlations reveal the shared genetic architecture of transcription in human peripheral blood

Lukowski, Samuel W.; Lloyd‐Jones, Luke R.; Holloway, Alexander; Kirsten, Holger; Hemani, Gibran; Yang, Jian; Small, Kerrin S.; Zhao, Jing Hua; Metspalu, Andres; Dermitzakis, Emmanouil T.; Gibson, Greg; Spector, Timothy D.; Thiery, Joachim; Scholz, Markus; Montgomery, Grant W.; Esko, Tõnu; Visscher, Peter M.; Powell, Joseph E.

doi:10.1038/s41467-017-00473-z

Cited by 21 publications

(20 citation statements)

References 34 publications

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“…The weak correlations between blood-based traits and growth traits limit the potential for blood-based traits to be used as indicators of performance under varying environments. Strong genetic correlations between blood-based traits indicate the existence of an important overlap in genetic control and can be considered as evidence of pleiotropic effects playing a role in regulating multiple blood-based traits as found previously by Lukowski et al (2017).…”

Section: Discussion Most Blood-based Traits and Growth Traits Are Weasupporting

confidence: 56%

Genetic Basis of Blood-Based Traits and Their Relationship With Performance and Environment in Beef Cattle at Weaning

Chinchilla-Vargas

Kramer

Tucker³

et al. 2020

Front. Genet.

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The objectives of this study were to explore the usefulness of blood-based traits as indicators of health and performance in beef cattle at weaning and identify the genetic basis underlying the different blood parameters obtained from complete blood counts (CBCs). Disease costs represent one of the main factors determining profitability in animal production. Previous research has observed associations between blood cell counts and an animal's health status in some species. CBC were recorded from approximately 570 Angus based, crossbred beef calves at weaning born between 2015 and 2016 and raised on toxic or novel tall fescue. The calves (N = ∼600) were genotyped at a density of 50k SNPs and the genotypes (N = 1160) were imputed to a density of 270k SNPs. Genetic parameters were estimated for 15 blood and 4 production. Finally, with the objective of identifying the genetic basis underlying the different blood-based traits, genome-wide association studies (GWAS) were performed for all traits. Heritability estimates ranged from 0.11 to 0.60, and generally weak phenotypic correlations and strong genetic correlations were observed among bloodbased traits only. Genome-wide association study identified ninety-one 1-Mb windows that accounted for 0.5% or more of the estimated genetic variance for at least 1 trait with 21 windows overlapping across two or more traits (explaining more than 0.5% of estimated genetic variance for two or more traits). Five candidate genes have been identified in the most interesting overlapping regions related to blood-based traits. Overall, this study represents one of the first efforts represented in scientific literature to identify the genetic basis of blood cell traits in beef cattle. The results presented in this study allow us to conclude that: (1) blood-based traits have weak phenotypic correlations but strong genetic correlations among themselves. (2) Blood-based traits have moderate to high heritability. (3) There is evidence of an important overlap of genetic control among similar blood-based traits which will allow for their use in improvement programs in beef cattle.

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Section: Discussion Most Blood-based Traits and Growth Traits Are Weasupporting

confidence: 56%

Genetic Basis of Blood-Based Traits and Their Relationship With Performance and Environment in Beef Cattle at Weaning

Chinchilla-Vargas

Kramer

Tucker³

et al. 2020

Front. Genet.

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“…First, Nath et al identified highly correlated groups of mRNA transcripts and metabolites (termed 'modules'), and performed genome-wide scans to associate specific SNPs with variation in each module 19 . In a related analysis, Lukowski et al demonstrated that mRNA transcripts with evidence for genetic correlations were more likely to be regulated by the same expression quantitative trait loci (eQTL) 36 . Finally, van der Wijst recently leveraged single-cell mRNA-seq data from 45 individuals to build personalized co-expression networks, and used these data to identify genetic variants that predicted interindividual variation in correlation structure 37 .…”

Section: Discussionmentioning

confidence: 99%

Genetic and environmental perturbations lead to regulatory decoherence

Lea

Subramaniam²,

et al. 2018

Preprint

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Correlation among traits is a fundamental feature of biological systems. From morphological characters, to transcriptional or metabolic networks, the correlations we routinely observe between traits reflect a shared regulation that remains poorly understood and difficult to study. To address this problem, we developed a new and flexible approach that allows us to identify factors associated with variation in correlation between individuals. Here, we use data from three large human cohorts to study the effects of genetic variation and environmental perturbation on correlations among mRNA transcripts and among NMR metabolites. We first show that environmental exposures (namely, infection and disease) lead to a systematic loss of correlation, which we define as 'decoherence'. Using longitudinal data, we show that decoherent metabolites are better predictors of whether someone will develop metabolic syndrome than metabolites commonly used as biomarkers of this disease. Finally, we show that correlation itself is a trait under genetic control: specifically, we mapped and replicated hundreds of 'correlation QTLs', which often involve transcription factors or their known target genes. Together, this work furthers our understanding of how and why coordinated biological processes break down, and highlights the role of decoherence in disease emergence.

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“…Similarly, Lukowski et al (2017) tested for genetic covariance between gene pairs, and identified 15,000 gene pairs (0.5% of all gene pairs) with significantly nonzero genetic covariance at 5% FDR [47]. Since effect on gene j acts through the regulatory network, effectively like a peripheral variant, although the GWAS signal itself would be found in cis to k. This effect would slightly increase the measured contribution of core gene variants to heritability, although it seems likely to be a modest effect unless core genes make up a large fraction of all genes.…”

Section: Core Gene Effects On Heritabilitymentioning

confidence: 98%

Trans effects on gene expression can drive omnigenic inheritance

Liu

Pritchard

2018

Preprint

145

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Early genome-wide association studies (GWAS) led to the surprising discovery that, for typical complex traits, the most significant genetic variants contribute only a small fraction of the estimated heritability. Instead, it has become clear that a huge number of common variants, each with tiny effects, explain most of the heritability. Previously, we argued that these patterns conflict with standard conceptual models, and that new models are needed. Here we provide a formal model in which genetic contributions to complex traits can be partitioned into direct effects from core genes, and indirect effects from peripheral genes acting as trans-regulators. We argue that the central importance of peripheral genes is a direct consequence of the large contribution of trans-acting variation to gene expression variation. In particular, we propose that if the core genes for a trait are co-regulated -as seems likely -then the effects of peripheral variation can be amplified by these co-regulated networks such that nearly all of the genetic variance is driven by peripheral genes. Thus our model proposes a framework for understanding key features of the architecture of complex traits.Key observations. As reviewed in our previous paper [10], a conceptual model of complex traits should allow for the following observations:

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Genetic correlations reveal the shared genetic architecture of transcription in human peripheral blood

Cited by 21 publications

References 34 publications

Genetic Basis of Blood-Based Traits and Their Relationship With Performance and Environment in Beef Cattle at Weaning

Genetic Basis of Blood-Based Traits and Their Relationship With Performance and Environment in Beef Cattle at Weaning

Genetic and environmental perturbations lead to regulatory decoherence

Trans effects on gene expression can drive omnigenic inheritance

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