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Including Phenotypic Causal Networks in Genome-Wide Association Studies Using Mixed Effects Structural Equation Models.

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.

SUBMITTER: Momen M

PROVIDER: S-EPMC6189326 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Including Phenotypic Causal Networks in Genome-Wide Association Studies Using Mixed Effects Structural Equation Models.

Momen Mehdi M Ayatollahi Mehrgardi Ahmad A Amiri Roudbar Mahmoud M Kranis Andreas A Mercuri Pinto Renan R Valente Bruno D BD Morota Gota G Rosa Guilherme J M GJM Gianola Daniel D

Frontiers in genetics 20181009

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 ...[more]

PMID: 30356716

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Project description:BackgroundThe effect of the cecal microbiome on growth of rabbits that were fed under different regimes has been studied previously. However, the term "effect" carries a causal meaning that can be confounded because of potential genetic associations between the microbiome and production traits. Structural equation models (SEM) can help disentangle such a complex interplay by decomposing the effect on a production trait into direct host genetics effects and indirect host genetic effects that are exerted through microbiota effects. These indirect effects can be estimated via structural coefficients that measure the effect of the microbiota on growth while the effects of the host genetics are kept constant. In this study, we applied the SEM approach to infer causal relationships between the cecal microbiota and growth of rabbits fed under ad libitum (ADGAL) or restricted feeding (ADGR).ResultsWe identified structural coefficients that are statistically different from 0 for 138 of the 946 operational taxonomic units (OTU) analyzed. However, only 15 and 38 of these 138 OTU had an effect greater than 0.2 phenotypic standard deviations (SD) on ADGAL and ADGR, respectively. Many of these OTU had a negative effect on both traits. The largest effects on ADGR were exerted by an OTU that is taxonomically assigned to the Desulfovibrio genus (- 1.929 g/d, CSS-normalized OTU units) and by an OTU that belongs to the Ruminococcaceae family (1.859 g/d, CSS-normalized OTU units). For ADGAL, the largest effect was from OTU that belong to the S24-7 family (- 1.907 g/d, CSS-normalized OTU units). In general, OTU that had a substantial effect had low to moderate estimates of heritability.ConclusionsDisentangling how direct and indirect effects act on production traits is relevant to fully describe the processes of mediation but also to understand how these traits change before considering the application of an external intervention aimed at changing a given microbial composition by blocking/promoting the presence of a particular microorganism.

Dataset Information

Including Phenotypic Causal Networks in Genome-Wide Association Studies Using Mixed Effects Structural Equation Models.

Publications

Including Phenotypic Causal Networks in Genome-Wide Association Studies Using Mixed Effects Structural Equation Models.

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