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October 11, 2023BMC GenomicsOpen Access

Summary-data based Mendelian randomization identifies gene expression regulatory polymorphisms associated with bovine paratuberculosis by modulation of the nuclear factor Kappa β (NF-κß)-mediated inflammatory response

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Key result

Mendelian randomization links two novel cis-eQTLs affecting EGR4 and MGC134040 to multifocal and diffuse gut lesions.

  • P=0.002
  • n=813

Why the study?

Most GWAS-identified SNPs associated with paratuberculosis susceptibility are in non-coding regions, and connecting these variants to affected genes remains challenging with few functional mutations or cis-eQTLs identified.

Population

16 Spanish Holstein cows for eQTL analysis and 813 culled cattle classified by PTB-associated gut lesions

Comparison

Integration of cis-eQTL dataset with GWAS data using summary-based Mendelian randomization

Design

Genomic and transcriptomic analysis with summary-data based Mendelian randomization

Authors

GBGerard Badia-BringuéMCMaría CaniveNFNora Fernández‐Jiménez

Discussion

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Overview

These eQTL associations are hypothesis-generating; leaves open validation of EGR4/MGC134040 effects before clinical consideration.

Structured PICO

P
Population
813 culled Holstein cows from Spain, classified by the presence or absence of paratuberculosis-associated histopathological lesions in gut tissues to identify genetic associations.
E
Exposure
Summary-based data Mendelian randomization (SMR) integrating cis-eQTL dataset with GWAS data
O
Outcome
Identification of cis-eQTLs affecting gene expression associated with the presence of multifocal and diffuse lesions in gut tissuessurrogate

Main Result

p-value: p=0.002

The study identifies novel regulatory SNPs and gene targets (EGR4 and MGC134040) associated with bovine paratuberculosis susceptibility, highlighting the role of NF-κß-mediated inflammatory response.

Limitations

  • Small sample size for the RNA-Seq and cis-eQTL mapping cohort (N=16).
  • The Tensor QTL algorithm only identifies cis-eQTLs within 1 Mb of a gene, potentially missing significant variants outside this range.
  • Lack of discrimination between focal lesions and controls in the GWAS limited findings for that specific outcome.
  • Further functional studies are needed to confirm the roles of MGC134040 and EGR4 in paratuberculosis susceptibility and resilience.

Cite This Study

Badia-Bringué et al. (2023) studied Bovine paratuberculosis (n=813). cis-eQTLs regulating EGR4 and MGC134040 expression vs. Absence of specific cis-eQTL variants was evaluated on Pleiotropic association with the presence of multifocal and diffuse lesions in gut tissues (p=0.002). Summary-based Mendelian randomization identified two novel cis-eQTLs affecting the expression of EGR4 and MGC134040 that showed pleiotropic associations with the presence of multifocal (P=0.002) and diffuse (P=0.017) gut lesions.

synapsesocial.com/papers/6ab21ae5a9ea7cbecff9329chttps://doi.org/10.1186/s12864-023-09710-w
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