Including phenotypic causal networks in genome-wide association studies using mixed effects structural equation models

Mehdi Momen, Ahmad Ayatollahi Mehrgardi, Mahmoud Amiri Roudbar, Andreas Kranis, Renan Mercuri Pinto, Bruno D. Valente, Gota Morota, Guilherme J.M. Rosa, Daniel Gianola

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Network based statistical models accounting for putative causal relationships among multiple phenotypes can be used to infer single-nucleotide polymorphism (SNP) effect which transmitting through a given causal path in genome-wide association studies (GWAS). In GWAS with multiple phenotypes, reconstructing underlying causal structures among traits and SNPs using a single statistical framework is essential for understanding the entirety of genotype-phenotype maps. A structural equation model (SEM) can be used for such purposes. We applied SEM to GWAS (SEM-GWAS) in chickens, taking into account putative causal relationships among breast meat (BM), body weight (BW), hen-house production (HHP), and SNPs. We assessed the performance of SEM-GWAS by comparing the model results with those obtained from traditional multi-trait association analyses (MTM-GWAS). Three different putative causal path diagrams were inferred from highest posterior density (HPD) intervals of 0.75, 0.85, and 0.95 using the inductive causation algorithm. A positive path coefficient was estimated for BM → BW, and negative values were obtained for BM → HHP and BW → HHP in all implemented scenarios. Further, the application of SEM-GWAS enabled the decomposition of SNP effects into direct, indirect, and total effects, identifying whether a SNP effect is acting directly or indirectly on a given trait. In contrast, MTM-GWAS only captured overall genetic effects on traits, which is equivalent to combining the direct and indirect SNP effects from SEM-GWAS. Although MTM-GWAS and SEM-GWAS use the similar probabilistic models, we provide evidence that SEM-GWAS captures complex relationships in terms of causal meaning and mediation and delivers a more comprehensive understanding of SNP effects compared to MTM-GWAS. Our results showed that SEM-GWAS provides important insight regarding the mechanism by which identified SNPs control traits by partitioning them into direct, indirect, and total SNP effects.

Original languageEnglish (US)
Article number455
JournalFrontiers in Genetics
Volume9
Issue numberOCT
DOIs
StatePublished - Oct 9 2018

Keywords

  • Causal structure
  • GWAS
  • Multiple traits
  • Path analysis
  • SEM
  • SNP effect

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Genetics(clinical)

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    Momen, M., Mehrgardi, A. A., Roudbar, M. A., Kranis, A., Pinto, R. M., Valente, B. D., Morota, G., Rosa, G. J. M., & Gianola, D. (2018). Including phenotypic causal networks in genome-wide association studies using mixed effects structural equation models. Frontiers in Genetics, 9(OCT), [455]. https://doi.org/10.3389/fgene.2018.00455