MR-GGI: accurate inference of gene-gene interactions using Mendelian randomization.

Publisher: BioMed Central Country of Publication: England NLM ID: 100965194 Publication Model: Electronic Cited Medium: Internet ISSN: 1471-2105 (Electronic) Linking ISSN: 14712105 NLM ISO Abbreviation: BMC Bioinformatics Subsets: MEDLINE

Original Publication: [London] : BioMed Central, 2000-

Mendelian Randomization Analysis* ; Polymorphism, Single Nucleotide*; Genome-Wide Association Study/methods ; Gene Regulatory Networks/genetics ; Epistasis, Genetic/genetics ; Quantitative Trait Loci ; Humans ; Saccharomyces cerevisiae/genetics

Background: Researchers have long studied the regulatory processes of genes to uncover their functions. Gene regulatory network analysis is one of the popular approaches for understanding these processes, requiring accurate identification of interactions among the genes to establish the gene regulatory network. Advances in genome-wide association studies and expression quantitative trait loci studies have led to a wealth of genomic data, facilitating more accurate inference of gene-gene interactions. However, unknown confounding factors may influence these interactions, making their interpretation complicated. Mendelian randomization (MR) has emerged as a valuable tool for causal inference in genetics, addressing confounding effects by estimating causal relationships using instrumental variables. In this paper, we propose a new statistical method, MR-GGI, for accurately inferring gene-gene interactions using Mendelian randomization.
Results: MR-GGI applies one gene as the exposure and another as the outcome, using causal cis-single-nucleotide polymorphisms as instrumental variables in the inverse-variance weighted MR model. Through simulations, we have demonstrated MR-GGI's ability to control type 1 error and maintain statistical power despite confounding effects. MR-GGI performed the best when compared to other methods using the F1 score on the DREAM5 dataset. Additionally, when applied to yeast genomic data, MR-GGI successfully identified six clusters. Through gene ontology analysis, we have confirmed that each cluster in our study performs distinct functional roles by gathering genes with specific functions.
Conclusion: These findings demonstrate that MR-GGI accurately inferences gene-gene interactions despite the confounding effects in real biological environments.
(© 2024. The Author(s).)

Genet Epidemiol. 2013 Nov;37(7):658-65. (PMID: 24114802)
Genet Epidemiol. 2016 May;40(4):304-14. (PMID: 27061298)
BMC Med Genomics. 2022 Apr 30;15(1):100. (PMID: 35501860)
Genet Epidemiol. 2014 Feb;38(2):123-34. (PMID: 24431225)
Am J Epidemiol. 2015 Feb 15;181(4):251-60. (PMID: 25632051)
Int J Epidemiol. 2015 Apr;44(2):512-25. (PMID: 26050253)
Stem Cell Res Ther. 2010 Dec 14;1(5):39. (PMID: 21156086)
Nat Genet. 2000 Apr;24(4):372-6. (PMID: 10742100)
J R Stat Soc Series B Stat Methodol. 2020 Dec;82(5):1273-1300. (PMID: 37220626)
Genetics. 2005 Feb;169(2):1133-46. (PMID: 15545647)
Elife. 2018 Jul 17;7:. (PMID: 30014850)
Nucleic Acids Res. 2004 Jan 1;32(Database issue):D311-4. (PMID: 14681421)
PLoS One. 2014 Mar 20;9(3):e92469. (PMID: 24651390)
Stat Methods Med Res. 2012 Jun;21(3):223-42. (PMID: 21216802)
BMC Med Imaging. 2015 Aug 12;15:29. (PMID: 26263899)
Front Genet. 2019 May 21;10:460. (PMID: 31164902)
Front Endocrinol (Lausanne). 2022 Aug 17;13:949061. (PMID: 36060942)
Nat Commun. 2019 Sep 19;10(1):4274. (PMID: 31537791)
BMC Bioinformatics. 2022 Feb 1;23(1):57. (PMID: 35105309)
PLoS Genet. 2022 Jul 19;18(7):e1010299. (PMID: 35853082)
Genet Epidemiol. 2021 Jun;45(4):353-371. (PMID: 33834509)
Cell Rep. 2018 Feb 27;22(9):2421-2430. (PMID: 29490277)

No. 2021R1F1A1054528 National Research Foundation of Korea(NRF) grant funded by the Korea government(MSIT); IITP-2023-2020-0-01789 MSIT(Ministry of Science and ICT), Korea, under the ITRC(Information Technology Research Center) support program

Keywords: Gene regulatory network; Gene–gene interactions; Mendelian randomization; Yeast GRN

Date Created: 20240515 Date Completed: 20240516 Latest Revision: 20240518

20240518

PMC11094870

10.1186/s12859-024-05808-4

38750431