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Cited by 523Genetic Associations and EpidemiologyGenetic and phenotypic traits in livestockGenetic Mapping and Diversity in Plants and Animals

Trans effects on gene expression can drive omnigenic inheritance

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Liu, Xuanyao, Li, Yang I., Pritchard, Jonathan K.·2019·Cell
DOI 10.1016/j.cell.2019.04.014PMC PMC6553491

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Abstract

Early genome-wide association studies (GWASs) led to the surprising discovery that, for typical complex traits, most of the heritability is due to huge numbers of common variants with tiny effect sizes. Previously, we argued that new models are needed to understand these patterns. Here, we provide a formal model in which genetic contributions to complex traits are partitioned into direct effects from core genes and indirect effects from peripheral genes acting in trans. We propose that most heritability is driven by weak trans-eQTL SNPs, whose effects are mediated through peripheral genes to impact the expression of core genes. In particular, if the core genes for a trait tend to be co-regulated, then the effects of peripheral variation can be amplified such that nearly all of the genetic variance is driven by weak trans effects. Thus, our model proposes a framework for understanding key features of the architecture of complex traits.

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  • Recent evidence from quantitative genetics in humans suggests that polygenic traits tend to be omnigenic; heritable variation in traits is not mainly due to a core biological process or pathway, but causative variants may act on almost any gene expressed in a relevant cell type, mediated by trans-regulatory variation.

    “Recent evidence from quantitative genetics (Boyle et al. 2017) in humans suggests that polygenic traits tend to be omnigenic. That is, heritable variation in traits is not mainly due to a core biological process or pathway, but causative variants may act on almost any gene expressed in a relevant cell type, mediated by trans-regulatory variation (Liu et al. 2019).”

    From The neural crest cell hypothesis: no unified explanation for domestication (2021) · cites this paper as Liu et al. 2019

  • APOE4 is a 'core' gene of AD pathogenesis in the sense that the strong effect on amyloid pathology, a core pathway of AD, explains the strong specific association with AD (odds ratio ~3.7-14.5).

    “Therefore, we propose that APOE4 is a “core” gene (Liu et al, 2019) of AD pathogenesis in the sense that the strong effect on amyloid pathology, a core pathway of AD, explains the strong specific association with AD (odds ratio ~3.7–14.5).”

    From APOE from astrocytes restores Alzheimer’s Aβ-pathology and DAM-like responses in APOE deficient microglia (2024) · cites this paper as Liu et al, 2019

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Cited by

Sorted by citations

Authors
Liu, X., Li, Y. I., & Pritchard, J. K.
Affiliations
  • University of Chicago (US)
  • Howard Hughes Medical Institute (US)
Corresponding author
  • Liu, Xuanyao
  • Li, Yang I.
  • Pritchard, Jonathan K.
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2019-05
Volume
177
Issue
4
Pages
1022-1034.e6
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2019.04.014
PMC
PMC6553491
OpenAlex
W2952835495
Cited by
523
References
16
Citations by year
2026: 45 · 2025: 65 · 2024: 96 · 2023: 62 · 2022: 59 · 2021: 70 · 2020: 87 · 2019: 37 · 2018: 2
FWCI
39.17
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Howard Hughes Medical Institute
  • National Institutes of Health (HG008140, HG009431)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and phenotypic traits in livestock
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
Keywords
trans-eQTL, heritability of gene expression, complex traits, core genes, co-regulation, genetic architecture
MeSH terms
Gene Expression Regulation, Humans, Models, Theoretical, Phenotype, Polymorphism, Genetic, Genetic Variation, Gene Expression, Multifactorial Inheritance, Gene Expression Profiling, Databases, Genetic, Quantitative Trait Loci, Heredity, Genome-Wide Association Study

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